WO2012155339A1 - 4-phenylamino-6-butenamide-7-alkyloxy quinazoline derivatives, preparative method and use thereof - Google Patents

Abstract

4-Phenylamino-6-butenamide-7-alkyloxy quinazoline derivatives, the preparative method thereof, the pharmaceutical composition comprising the derivatives, and the use of them in manufacturing medicaments for treatment diseases related to tyrosine protein kinase. The diseases include breast cancer, colorectal cancer, lung cancer and the like.

Description

4-苯胺 -6-丁烯酰胺 -7-烷醚喹唑啉衍生物及其制备方法和用途 技术领域  4-aniline-6-butenamide -7-alkyl ether quinazoline derivative and preparation method and use thereof

本发明涉及医药领域， 特别涉及 4-苯胺 -6-丁烯酰胺 -7-烷醚喹唑啉类 衍生物及其制备方法及含有该衍生物的药物组合物以及其作为治疗剂特 别是作为 erbB家族蛋白酪氨酸激酶（PTK )抑制剂的用途。 背景技术  The present invention relates to the field of medicine, and in particular to 4-aniline-6-butenamide-7-alkyl ether quinazoline derivatives, a preparation method thereof, and a pharmaceutical composition containing the same, and as a therapeutic agent, particularly as erbB Use of family protein tyrosine kinase (PTK) inhibitors. Background technique

细胞信号传导是一种基础的作用机制。在信号传导过程中，来自细胞 外的刺激被传递到细胞内部，进而调节细胞的不同过程。这些受信号调节 的过程包括细胞增殖、 分化、 凋亡和运动等。很多信号传递是通过生长因 子与 PTK跨膜受体酪氨酸蛋白激酶（RTK ) 结合来调节细胞内的过程。  Cell signaling is a fundamental mechanism of action. During signal transduction, extracellular stimuli are transmitted to the interior of the cell, which in turn regulates the different processes of the cell. These signal-regulated processes include cell proliferation, differentiation, apoptosis, and exercise. Many signaling is regulated by the growth factor binding to the PTK transmembrane receptor tyrosine protein kinase (RTK) to regulate intracellular processes.

许多 RTK的不适当的或不受控制的激活， 即异常的 RTK活性， 例如 过高的表达或突变将导致细胞生长或分化等不受正常的控制，从而导致疾 病。 已知因 RTK异常活性所导致的疾病有牛皮癣， 类风湿关节炎， 多种 癌症， 以及血管生成、 粥状动脉硬化等疾病。 RTK有多个亚族， 其中一 个亚族是 erbB激酶家族， 成员包括 EGFr (又名 ErbBl )、 HER2 (又名 ErbB2 ), HER3 (又名 ErbB3 )和 HER4 (又名 ErbB4 )„ 这些 RTK由细 胞外糖基化配体结合域、跨膜域和可将蛋白质上酪氨酸序列进行磷酰化的 细胞内细胞质催化域组成。其中 HER3不含有能将蛋白质上酪氨酸序列进 行磷酰化的细胞内细胞质催化域。 RTK 的催化活性可通过受体过度表达 或配体介导二聚合而激活。 ErbB家族 RTKs聚合体有同型二聚体和异型 二聚体两种形式。 同型二聚体一个例子为 EGFr和 EGF家族配体（包括 EGF、转化生长因子、 betacellulin, epiregulin等）的聚合。 ErbB家族 RTKs 之间的异体二聚合可通过 heregulin (又名 neuregulin ) 家族配体结合而加 速。 HER3虽然没有受体激酶活性， 但其与 HER2或 HER4的异型二聚可 显著刺激受体激酶的聚合及酪氨酸磷酰化催化活性。研究发现 EGFr的过 度激活与一些过度增生的疾病如非小细胞肺癌、膀胱癌、 头颈部癌， 脑癌 等有潜在的关系， 而增强的 HER2活性已经涉及到***癌、子宫癌、 卵巢 癌、胃癌及胰腺癌等癌症。因此抑制 erbB家族 RTKs可以提供以异常 erbB 家族 RTK活性为特征的疾病的治疗。 已有多篇文献讨论 erbB家族 RTK 的生物学作用， 及其与各种疾病的关系， 如以下文献和专利： Reid, A.， et al. Eur. J. Cancer, 2007, 43, 481 ; Doebele, R.C., et al. Lung Cancer. 2010, 69, 1-12; Ocana, A.; Amir, E. Cancer Treat Rev. 2009, 35, 685-91 ; Minkovsky, N. et al. Current Opinion in Investigational Drugs 2008, 9, 1336-1346; WO2002/66445, WO 1999/09016, US06627634等。 Inappropriate or uncontrolled activation of many RTKs, ie abnormal RTK activity, such as excessive expression or mutation, will result in uncontrolled cell growth or differentiation, leading to disease. Diseases caused by abnormal activity of RTK are known to have psoriasis, rheumatoid arthritis, various cancers, and diseases such as angiogenesis and atherosclerosis. RTK has multiple subfamilies, one of which is the erbB kinase family, which includes EGFr (aka ErbBl), HER2 (aka ErbB2), HER3 (aka ErbB3), and HER4 (aka ErbB4). These RTKs are composed of cells. An extracellular glycosylation ligand binding domain, a transmembrane domain, and an intracellular cytoplasmic catalytic domain that phosphorylates a tyrosine sequence on a protein. HER3 does not contain a phosphorylation of a tyrosine sequence on a protein. Intracellular cytoplasmic catalytic domain. The catalytic activity of RTK can be activated by receptor overexpression or ligand-mediated dimerization. ErbB family RTKs aggregates have both homodimer and heterodimer forms. Examples are the polymerization of EGFr and EGF family ligands (including EGF, transforming growth factor, betacellulin, epiregulin, etc.) Allodimerization between ErbB family RTKs can be accelerated by the binding of heregulin (aka neuregulin) family of ligands. There is no receptor kinase activity, but its heterodimerization with HER2 or HER4 can significantly stimulate the polymerization of receptor kinase and the catalytic activity of tyrosine phosphorylation. Studies have found that EGFr over-activation and some Proliferative diseases such as non-small cell lung cancer, bladder cancer, head and neck cancer, brain cancer, etc. have a potential relationship, and enhanced HER2 activity has been involved in breast cancer, uterine cancer, ovarian cancer, stomach cancer and pancreatic cancer. Inhibition of erbB family RTKs can provide abnormal erbB Treatment of diseases characterized by family RTK activity. A number of papers have been discussed on the biological role of the erbB family of RTKs and their relationship to various diseases, such as the following literature and patents: Reid, A., et al. Eur. J. Cancer, 2007, 43, 481 ; Doebele , RC, et al. Lung Cancer. 2010, 69, 1-12; Ocana, A.; Amir, E. Cancer Treat Rev. 2009, 35, 685-91; Minkovsky, N. et al. Current Opinion in Investigational Drugs 2008, 9, 1336-1346; WO2002/66445, WO 1999/09016, US06627634 and the like.

许多专利文献中讨论了 RTK抑制剂或喹唑啉衍生物的相关技术， 如 WO9630347 (中国专利申请 CN96102992.7 )涉及一些 4-苯基胺喹唑啉类 化合物用于治疗过度增生疾病。 W09738973 (中国专利申请 CN97194458 ) 和 WO2009/140863 (中国专利申请 CN2009000557 )公开了作为酪氨酸激 酶不可逆抑制剂的制备和药物用途。 WO0006555 ( 中国专利申请 CN99808949 )公布了有关取代的喹唑啉衍生物具有抑制 RTK活性的功 能。 W09935146 (中国专利申请 CN99803887 )披露了一系列的二环芳香 杂环包括喹唑啉化合物为 RTK 激酶抑制剂。 另外， 中国专利申请如 CN01817895 , CN93103556 , CN98807303 , CN96193526 , CN01812051 , CN99803887 , CN0410089867 , CN03811739 ; 美国专利如 US5521884, US6894051 , US6958335 , US5457105 , US5616582 , US5770599 , US5747498 , US6900221 , US6391874 , US6713485 , US6727256 , US6828320 , US7157466 中均提及多种喹唑啉类化合物具有抑制多种 RTK活性的功能。 已经有数个喹唑啉类激酶抑制剂药物被美国、 欧洲等 多个国家和地区批准上市用于治疗癌症， 例如 Gefitinib (商品名 Irresa ), Erlotinib (商品名 Tarceva ), Lapatinib (商品名 Tykerb )等。 随着生物机 理的研究、 医学诊断和肿瘤治疗水平的不断提高， 对增生类疾病， 尤其是 肿瘤的治疗趋向于细化、靶向化和病人个体化。 因此开发疗效明确、靶向 性高的抗增生类疾病和癌症的化合物仍然是临床应用所急需。 发明内容  A related art of RTK inhibitors or quinazoline derivatives is discussed in many patent documents, such as WO9630347 (Chinese Patent Application CN96102992.7), which relates to the use of some 4-phenylamine quinazolines for the treatment of hyperproliferative diseases. The preparation and pharmaceutical use as an irreversible inhibitor of tyrosine kinase are disclosed in WO0973843 (Chinese Patent Application No. CN97194458) and WO2009/140863 (Chinese Patent Application No. CN2009000557). WO0006555 (Chinese Patent Application CN99808949) discloses a function of inhibiting RTK activity in a substituted quinazoline derivative. W09935146 (Chinese Patent Application CN99803887) discloses a series of bicyclic aromatic heterocycles including quinazoline compounds as RTK kinase inhibitors. In addition, Chinese patent applications such as CN01817895, CN93103556, CN98807303, CN96193526, CN01812051, CN99803887, CN0410089867, CN03811739; US patents such as US5521884, US6894051, US6958335, US5457105, US5616582, US5770599, US5747498, US6900221, US6391874, US6713485, US6727256, US6828320, US7157466 It is mentioned that a plurality of quinazoline compounds have a function of inhibiting various RTK activities. Several quinazoline kinase inhibitor drugs have been approved for use in the treatment of cancer in the United States, Europe and other countries, such as Gefitinib (trade name Irresa), Erlotinib (trade name Tarceva), Lapatinib (trade name Tykerb), etc. . With the continuous improvement of biological mechanism research, medical diagnosis and tumor treatment, the treatment of proliferative diseases, especially tumors, tends to be refined, targeted and individualized. Therefore, the development of compounds with clear curative effects and high targeting of anti-proliferative diseases and cancers is still urgently needed for clinical applications. Summary of the invention

本发明的目的在于提供通式（I )所示的新的喹唑啉类化合物， 或其 立体异构体、 几何异构体、 互变异构体、 水合物、 溶剂化物、 多晶型物、 代谢产物、 药学上可接受

The object of the present invention is to provide a novel quinazoline compound represented by the formula (I), or a stereoisomer, a geometric isomer, a tautomer, a hydrate, a solvate or a polymorph thereof. , Metabolite, pharmaceutically acceptable

其中： Ar是被取代的单环苯基或单环芳香杂环基， 可以被 0-4个卤素， 三氟曱基， 三氟曱氧基， C_w烷基， 乙炔基， 乙烯基， 烷氧基， 或 ( CH^Ar¹所取代， 其中 n是 0或 1； Wherein: Ar is a substituted phenyl or a monocyclic aromatic monocyclic heterocyclic group, substituted with 0-4 halo, trifluoromethyl group Yue, Yue trifluoromethyl group, C _w-alkyl, ethynyl, vinyl, alkoxy Oxy, or (CH^Ar ¹ substituted, wherein n is 0 or 1;

Ar¹选自单环芳香环或 5-6元芳香杂环， 并且芳香环或芳香杂环可以 被 0-3个卤素， 三氟曱基， 三氟曱氧基， C_1-3烷基， C_2-3炔基， C_2-3烯基, 烷氧基所取代； Ar ^{1 is} selected from a monocyclic aromatic ring or a 5-6 membered aromatic heterocyclic ring, and the aromatic ring or the aromatic heterocyclic ring may be 0-3 halogen, trifluorodecyl, trifluoromethoxy, C _1-3 alkyl, C _2-3 alkynyl, C _2-3 alkenyl, substituted by alkoxy;

L选自 （CH₂ ) _m, 其中 m是 0或 1 ; L is selected from (CH ₂ ) _m , wherein m is 0 or 1;

M是一个 6-10元双环烷基杂环， 杂环内含一个或多个 0, N, 或 S 原子， 并且杂环上可以进一步被一个或多个 素， 烷基， 羟基， 或 烷氧基所取代。  M is a 6-10 membered bicycloalkylheterocyclic ring containing one or more 0, N, or S atoms, and the heterocyclic ring may be further protected by one or more of an element, an alkyl group, a hydroxyl group, or an alkoxy group. Substituted by the base.

进一步， 通式（I ) 中优选的 Ar  Further, preferred Ar in the general formula (I)

具体地， 通式（I )所述的化合物或其盐包括， 但不限于表 1所述化合物:

Specifically, the compound of the formula (I) or a salt thereof includes, but is not limited to, the compound described in Table 1:

其中， 所述的盐为上述化合物与以下的酸形成的盐： 苹果酸， 乳酸, 马来酸， 富马酸， 琥珀酸， 盐酸， 曱磺酸， 曱苯橫酸， 苯橫酸， 硫酸， 磷酸， 柠檬酸， 酒石酸， 乙酸， 丙酸， 辛酸， 己酸， 苯曱酸。  Wherein the salt is a salt of the above compound with the following acid: malic acid, lactic acid, maleic acid, fumaric acid, succinic acid, hydrochloric acid, sulfonic acid, terpene phthalic acid, benzoic acid, sulfuric acid, Phosphoric acid, citric acid, tartaric acid, acetic acid, propionic acid, caprylic acid, caproic acid, benzoic acid.

本发明的一个方面是提供一种药物组合物， 含有通式（I )所示的化 合物，或其药学上可接受的盐或其前药和药学上可接受的载体或赋形剂以 及其在制备治疗与受体酪氨酸蛋白激酶有关的疾病的药物或受体酪氨酸 蛋白激酶抑制剂特别是作为 erbB 家族受体酪氨酸蛋白激酶抑制剂的用 途。所述受体酪氨酸蛋白激酶有关疾病包括但不限于乳腺癌，结肠直肠癌， 肺癌， ***状癌， ***癌， 淋巴瘤， 结肠癌， 胰腺癌， 卵巢癌， 子宫颈 癌， 中枢神经***癌， 成骨肉瘤， 肾癌， 肝癌， 膀胱癌， 胃癌， 头或颈鳞 癌， 黑色素瘤和白血病。 One aspect of the present invention provides a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof or a prodrug thereof, and a pharmaceutically acceptable carrier or excipient, and Preparation of a drug or receptor tyrosine for the treatment of a disease associated with a receptor tyrosine protein kinase Protein kinase inhibitors are particularly useful as inhibitors of the erbB family of receptor tyrosine protein kinases. The receptor tyrosine protein kinase-related diseases include, but are not limited to, breast cancer, colorectal cancer, lung cancer, papillary carcinoma, prostate cancer, lymphoma, colon cancer, pancreatic cancer, ovarian cancer, cervical cancer, central nervous system Cancer, osteosarcoma, kidney cancer, liver cancer, bladder cancer, stomach cancer, head or neck squamous cell carcinoma, melanoma and leukemia.

本发明的另一个方面是提供一种受体蛋白质酪氨酸激酶（ RTK )调节 方法， 包括使 RTK和通式（I ) 的化合物或其药学上可接受的盐相结合。  Another aspect of the invention provides a method of modulating a receptor protein tyrosine kinase (RTK) comprising combining RTK with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

本发明的另一个方面是提供一种制备通式（I )化合物的方法。 所述 方法包括下列步骤：  Another aspect of the invention provides a process for the preparation of a compound of formula (I). The method includes the following steps:

步骤 1 :化合物 la与苯胺化合物 ArNH₂进行取代反应得到化合物 lb; 步骤 2: 醇 M— L一 OH用强碱处理后加入化合物 lb得到化合物 Ic; 步骤 3: 化合物 Ic发生还原反应生成 Id; Step 1: Compound la is substituted with aniline compound ArNH ₂ to obtain compound lb; Step 2: alcohol M-L-OH is treated with strong base and compound lb is added to obtain compound Ic; Step 3: Compound Ic undergoes reduction reaction to form Id;

步骤 4: Id与酸 Ie在偶联试剂作用下进行酰胺化反应生成化合物 If; 步骤 5: 化合物 If 和 2-二曱胺乙醛进行维悌希反应生成通式（I )化 合物；

Step 4: Id and acid Ie are amidated by a coupling reagent to form compound If; Step 5: Compound If and 2-diamine acetaldehyde are subjected to Wittig reaction to form a compound of formula (I);

其中， Ar是被取代的单环苯基或单环芳香杂环基， 可以被 0-4个卤 素， 三氟曱基， 三氟曱氧基， C_1-3烷基所取代， 乙炔基， 乙烯基， C_1-3烷 氧基， 或 O CH^Ar¹所取代， 其中 n是 0或 1 ; Wherein Ar is a substituted monocyclic phenyl or monocyclic aromatic heterocyclic group which may be substituted by 0-4 halogen, trifluoromethyl, trifluoromethoxy, C _1-3 alkyl, ethynyl, Substituted by a vinyl group, a C _1-3 alkoxy group, or O CH^Ar ¹ wherein n is 0 or 1;

Ar¹选自单环芳香环或 5-6元芳香杂环， 并且芳香环或芳香杂环可以 被 0-3个卤素， 三氟曱基， 三氟曱氧基， C_1-3烷基， C_2-3炔基， C_2-3烯基， 烷氧基所取代； Ar ^{1 is} selected from a monocyclic aromatic ring or a 5-6 membered aromatic heterocyclic ring, and the aromatic ring or the aromatic heterocyclic ring may be 0-3 halogen, trifluorodecyl, trifluoromethoxy, C _1-3 alkyl, C _2-3 alkynyl, C _2-3 alkenyl, substituted by alkoxy;

L选自单键或 CH₂; M是一个 6-10元双环烷基杂环， 杂环内含一个或多个 0, N, 或 S 原子， 并且杂环上可以进一步被一个或多个卤素， C_w烷基， 羟基， 或 烷氧基所取代。 L is selected from a single bond or CH ₂ ; M is a 6-10 membered bicycloalkyl heterocycle containing one or more 0, N, or S atoms, and the heterocycle may be further substituted with one or more halogens, C _w alkyl, hydroxy, or Substituted by an alkoxy group.

作为优选， 步骤 2所述强碱为氢化钠； 更优选的， 步骤 3所述还原为 铂-碳催化氢化， 铁粉-酸催化。  Preferably, the strong base in step 2 is sodium hydride; more preferably, the reduction in step 3 is platinum-carbon catalytic hydrogenation, iron powder-acid catalysis.

4-氯喹唑啉化合物 la (文献： Rewcastle, G.W., et al. J. Med.  4-chloroquinazoline compound la (Reference: Rewcastle, G.W., et al. J. Med.

Chem., 1996 , vol. 39, 918 - 928 ) 与苯胺化合物进行取代反应得到化 合物 Ib。 相应的醇 M— L一 OH用强碱（氢化钠）处理后， 将化合物 lb 加入。 由此得到的化合物 Ic被还原成胺 Id。 还原方法有铂-碳催化氢化， 铁粉-酸等。 所得的胺 Id在偶联试剂如 CDI (Ν,Ν'-Carbonyldiimidazole)作 用下， 与酸 Ie进行酰胺化反应生成化合物 If。 化合物 If 和由新制备得的 2-二曱胺乙醛进行维悌希 （Wittig )反应， 生成通式（I )化合物。 Chem., 1996, vol. 39, 918 - 928) The substitution reaction with an aniline compound gives the compound Ib. After the corresponding alcohol M-L-OH is treated with a strong base (sodium hydride), compound lb is added. The compound Ic thus obtained is reduced to the amine Id. The reduction methods include platinum-carbon catalytic hydrogenation, iron powder-acid, and the like. The resulting amine Id is amidated with an acid Ie to form a compound If under a coupling reagent such as CDI (Ν,Ν'-Carbonyldiimidazole). The compound If and the newly prepared 2-diamine acetaldehyde are subjected to a Wittig reaction to form a compound of the formula (I).

本发明的另一个方面是提供一种使用通式（I )所述的化合物或药物 组合物治疗与受体酪氨酸蛋白激酶有关疾病的方法，包括给予患者所述化 合物或药物组合物的有效治疗量。 发明的详细说明  Another aspect of the present invention provides a method of treating a disease associated with a receptor tyrosine protein kinase using the compound or pharmaceutical composition of the formula (I), comprising administering to the patient an effective effect of the compound or pharmaceutical composition The amount of treatment. Detailed description of the invention

除非特地指出， 在说明书和权利要求书中使用的术语具有以下含义。 像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基 所取代， 如上面的通式化合物， 或者像实施例里面特殊的例子， 子类， 和 本发明所包含的一类化合物。 应了解"任选取代的"这个术语与"取代或非 取代的 "这个术语可以交换使用。 一般而言， 术语"任选地"不论是否位于 术语"取代的"之前，表示所给结构中的一个或多个氢原子被具体取代基所 取代。除非其他方面表明，一个任选的取代基团可以有一个取代基在基团 各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自 具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各 个位置取代。其中所述的取代基可以是，但并不限于，羟基，氨基， 卤素， 氰基， 芳基， 杂芳基， 烷氧基， 烷基， 烯基， 炔基， 杂环基， 巯基， 硝基， 芳氧基等等。 "烷基"指饱和的烃基团， 包括 1到 20个碳原子的直链和支链基团。 优选含有 1到 6个碳原子的烷基， 例如曱基、 乙基、 丙基、 异丙基、 正丁 基、 异丁基、叔丁基、 戊基等。 更优选的是含有 1到 3个碳原子的低级烷 基，例如曱基、 乙基、 丙基、异丙基。烷基可以是被取代的或未被取代的， 当被取代时， 取代基优选为一个或多个， 独立地选自羟基、 卤素等。 Unless otherwise stated, terms used in the specification and claims have the following meanings. As described herein, the compounds of the invention may be optionally substituted with one or more substituents, such as the compounds of the above formula, or, as in the examples, specific examples, subclasses, and inclusions of the invention A class of compounds. It should be understood that the term "optionally substituted" and the term "substituted or unsubstituted" are used interchangeably. In general, the term "optionally" whether preceded by the term "substituted" means that one or more hydrogen atoms in a given structure are replaced by a particular substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substitutable position of the group. When more than one position in the given formula can be substituted by one or more substituents selected from a particular group, the substituents may be substituted at the various positions, either identically or differently. The substituents described therein may be, but are not limited to, hydroxy, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkyl, alkenyl, alkynyl, heterocyclic, fluorenyl, nitro Base, aryloxy and the like. "Alkyl" means a saturated hydrocarbon group including straight chain and branched chain groups of 1 to 20 carbon atoms. An alkyl group having 1 to 6 carbon atoms such as an anthracenyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a t-butyl group, a pentyl group or the like is preferable. More preferred are lower alkyl groups having 1 to 3 carbon atoms, such as an anthracenyl group, an ethyl group, a propyl group, and an isopropyl group. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more, independently selected from a hydroxyl group, a halogen, and the like.

"芳香基"是指具有至少有一个芳环结构的基团，即具有共轭的 π电子 体系的芳环。  "Aromatic group" means a group having at least one aromatic ring structure, that is, an aromatic ring having a conjugated π-electron system.

"芳香杂环基"指具有 1到 3个杂原子环原子，其余环原子为碳的芳基。 "Aromatic heterocyclic group" means an aryl group having 1 to 3 hetero atom ring atoms, and the remaining ring atoms being carbon.

"双环烷基杂环"指含有两个环的连环或稠环基团， 至少有 6-10个环 原子， 其中 1到 3个环原子选自氮、 氧或 S(0)_n (其中 η是整数 0-2 ) 的 杂原子， 其余环原子为碳。 这些环还可以有一个或多个双键。 这些环可以 是取代的或未取代的。 当被取代时，取代基优选为一个或多个， 更优选为 一个、 两个或三个， 进而优选为一个或两个， 独立地选自^ 级烷基、 三氟 曱基、 卤素、 羟基、 低级烷氧基、 氰基等。 "Bicycloalkylheterocycle" means a bicyclic or fused ring group containing two rings, having at least 6-10 ring atoms, wherein 1 to 3 ring atoms are selected from nitrogen, oxygen or S(0) _n (where η Is a hetero atom of the integer 0-2), and the remaining ring atoms are carbon. These rings can also have one or more double bonds. These rings may be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, further preferably one or two, independently selected from the group consisting of alkyl, trifluoromethyl, halogen, hydroxy , lower alkoxy, cyano, and the like.

"卤素"指氟、 氯、 溴、 碘。 优选的卤素为氟和氯。  "Halogen" means fluoro, chloro, bromo, iodo. Preferred halogens are fluorine and chlorine.

"羟基 "是指 "一OH"基团。  "Hydroxy" means an "mono-OH" group.

"烷氧基"指"一 0— (烷基 ) ", 代表性实施例包括但不限制于曱氧基、 乙氧基、 丙氧基、 环丙氧基、 丁氧基、 环丁氧基等。  "Alkoxy" means "mono-(alkyl)", and representative examples include, but are not limited to, decyloxy, ethoxy, propoxy, cyclopropoxy, butoxy, cyclobutoxy Wait.

"可选 "代表随后所描述的事件或环境可以但不必发生。  "Optional" means that the event or environment described later may, but need not, occur.

"药物组合物 "表示一种或多种本文所述化合物或其药学上可以接受 的盐或前药与其他化合物组成的混合物，其他组分例如生理学或药学可接 受的载体或赋形剂。 药物组合物的目的是促进化合物对生物的给药。  "Pharmaceutical composition" means a mixture of one or more of the compounds described herein, or a pharmaceutically acceptable salt or prodrug thereof, with other compounds, such as a physiologically or pharmaceutically acceptable carrier or excipient. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.

除非其他方面表明， 本发明所描述的结构式包括所有的同分异构形 式（如对映异构， 非对映异构， 和几何异构（或构象异构））： 例如含有不 对称中心的 R、 S构型， 双键的 (Z)、 （E)异构体， 和 (Z)、 （E)的构象异构 体。 因此， 本发明的化合物的单个立体化学异构体或其对映异构体， 非对 映异构体，或几何异构体（或构象异构体 )的混合物都属于本发明的范围。  Unless otherwise indicated, the structural formulae described herein include all isomeric forms (e.g., enantiomeric, diastereomeric, and geometric (or conformational)): for example, containing asymmetric centers R, S configuration, (Z), (E) isomers of double bonds, and (Z), (E) conformers. Thus, individual stereochemical isomers of the compounds of the invention, or enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers) of the compounds of the invention are within the scope of the invention.

本发明所使用的术语 "互变异构体 "或"互变异构形式"表示具有不同 能量的结构同分异构体可以越过低能垒， 从而互相转化。 譬如，质子互变 异构体（即质子移变） 包括通过质子迁移进行互变， 如酮-烯醇式互变和 亚胺-烯胺同分异构化作用。 化合价互变异构体包括通过一些成键电子重 组而进行互变。 The term "tautomer" or "tautomeric form" as used in the present invention means that structural isomers having different energies can cross the low energy barrier and thereby transform each other. For example, proton interaction Isomers (i.e., proton shifts) include interconversions by proton transfer, such as keto-enol interconversion and imine-enamine isomerization. Valence tautomers include interconversion through some bonding electron recombination.

除非其他方面表明，本发明的化合物的所有互变异构形式都包含在本 发明的范围之内。  Unless otherwise indicated, all tautomeric forms of the compounds of the invention are included within the scope of the invention.

本发明所使用的术语 "前药"，代表一个化合物在体内转化为式 (I)所示 的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转 化为母体结构的影响。  The term "prodrug" as used in the present invention denotes a compound which is converted in vivo to a compound of the formula (I). Such transformation is effected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in blood or tissue.

"代谢产物"是指具体的化合物或其盐在体内通过代谢作用所得到的 产物。 一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定， 其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的 产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用， 酯化， 脱脂作用， 酶裂解等等方法得到。 相应地， 本发明包括化合物的代 谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代 谢产物。  "Metabolic product" means a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of a compound can be identified by techniques well known in the art, and the activity can be characterized by experimental methods as described herein. Such products may be obtained by oxidative, reducing, hydrolyzing, amidating, deamidating, esterifying, defatting, enzymatic cleavage, etc., by administration of the compound. Accordingly, the invention includes metathesis products of the compounds, including the metabolites produced by intimate contact of the compounds of the invention with a mammal for a period of time.

本发明的化合物可以包含不对称中心或手性中心，因此存在不同的立 体异构体。 本发明的化合物所有的立体异构形式， 包括但绝不限于， 非对 映体， 对映异构体， 阻转异构体， 和它们的混合物， 如外消旋混合物， 组 成了本发明的一部分。很多有机化合物都以光学活性形式存在， 即它们有 能力旋转平面偏振光的平面。在描述光学活性化合物时，前缀 D、 1^或1、 S用来表示分子手性中心的绝对构型。 前缀 d、 1或（ + )、 （- )用来命名化 合物平面偏振光旋转的符号， （- )或 1是指化合物是左旋的， 前缀（+ ) 或 d是指化合物是右旋的。这些立体异构体的化学结构是相同的，但是它 们的立体结构不一样。特定的立体异构体可以是对映体，异构体的混合物 通常称为对映异构体混合物。 50: 50的对映体混合物被称为外消旋混合 物或外消旋体， 这可能导致化学反应过程中没有立体选择性或立体定向 性。术语"外消旋混合物 "和"外消旋体"是指等摩尔的两个对映异构体的混 合物， 缺乏光学活性。  The compounds of the invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomers. All stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers, atropisomers, and mixtures thereof, such as racemic mixtures, constitute the present invention. portion. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate planes of plane polarized light. In describing an optically active compound, the prefix D, 1^ or 1, S is used to indicate the absolute configuration of the molecular chiral center. The prefix d, 1 or ( + ), (- ) is used to designate the sign of the plane-polarized light rotation of the compound, (-) or 1 means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed. The chemical structures of these stereoisomers are the same, but their stereostructures are different. A particular stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as a mixture of enantiomers. The 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during the chemical reaction. The terms "racemic mixture" and "racemate" mean an equimolar mixture of two enantiomers which lacks optical activity.

术语"互变异构体"或"互变异构的形式"是指不同能量的结构的同分 异构体可以通过低能垒互相转化。例如质子互变异构体（即质子移变的互 变异构体）包括通过质子迁移的互变， 如酮式-烯醇式和亚胺 -烯胺的同分 异构化作用。 原子价（化合价） 互变异构体包括重组成键电子的互变。 The term "tautomer" or "tautomeric form" refers to the identity of structures of different energies. Isomers can be converted into each other by a low energy barrier. For example, proton tautomers (i.e., proton-shifted tautomers) include interconversions by proton transfer, such as keto-enol and imine-enamine isomerization. Atomic valence (valence) Tautomers include the interconversion of recombination bond electrons.

本发明所使用的 "药学上可接受的盐 "是指本发明的化合物的有机盐 和无机盐。 药学上可接受的盐在所属领域是为我们所熟知的。  The "pharmaceutically acceptable salt" as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention. Pharmaceutically acceptable salts are well known in the art.

药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反 应形成的无机酸盐有盐酸盐， 氢溴酸盐， 磷酸盐， 硫酸盐， 硝酸盐， 和有 机酸盐如乙酸盐， 草酸盐， 马来酸盐， 酒石酸盐， 柠檬酸盐， 琥珀酸盐， 丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些 盐。 其他药学上可接受的盐包括己二酸盐， 藻酸盐， 抗坏血酸盐， 天冬氨 酸盐， 苯蹟酸盐， 苯曱酸盐， 重 酸盐， 硼酸盐， 丁酸盐， 樟脑酸盐， 樟 脑横酸盐， 环戊基丙酸盐， 二葡萄糖酸盐， 十二烷基硫酸盐， 乙磺酸盐, 曱酸盐， 反丁烯二酸盐， 葡庚糖酸盐， 甘油磷酸盐， 葡萄糖酸盐， 半硫酸 盐， 庚酸盐， 己酸盐， 氢碘酸盐， 2-羟基 -乙蹟酸盐， 乳糖醛酸盐， 乳酸 盐， 月桂酸盐， 月桂基硫酸盐， 苹果酸盐， 丙二酸盐， 曱磺酸盐， 2-蔡蹟 酸盐， 烟酸盐， 硝酸盐， 油酸盐， 棕榈酸盐， 朴酸盐， 果胶酸盐， 过^ 酸 盐， 3-苯基丙酸盐， 苦味酸盐， 特戊酸盐， 丙酸盐， 硬脂酸盐， 硫氰酸盐， 对曱苯蹟酸盐， 十一酸盐， 戊酸盐， 等等。 通过适当的碱得到的盐包括碱 金属， 碱土金属， 铵和 N+(C_M烷基 )₄的盐。 本发明也拟构思了任何所包 含 N的基团的化合物所形成的季铵盐。 水溶性或油溶性或分散产物可以 通过季铵化作用得到。 碱金属或碱土金属盐包括钠， 锂， 钾， 钙， 镁， 等 等。 药学上可接受的盐进一步包括适当的、无毒的铵， 季铵盐和抗平衡离 子形成的胺阳离子，如卤化物， 氢氧化物，羧化物，硫酸化物，磷酸化物， 硝酸化物， 磺酸化物和芳香磺酸化物。 Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, mineral acid salts formed by reaction with amino groups, hydrochloride, hydrobromide, phosphate, sulfate, nitrate, and organic Acid salts such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or other methods such as ion exchange to obtain these salts. . Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzoate, benzoate, dibasic acid, borate, butyrate, camphoric acid Salt, camphorate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, citrate, fumarate, glucoheptonate, glycerol phosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethyl ester, lactoboxylate, lactate, laurate, lauryl sulfate, Malate, malonate, sulfonate, 2-toxin, nicotinate, nitrate, oleate, palmitate, palmitate, pectinate, peroxylate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-nonyl sulphate, eldecanoate, valerate, and the like. Salts obtained by appropriate bases include the alkali metal, alkaline earth metal, ammonium and N+(C _M alkyl) ₄ salts. The present invention also contemplates quaternary ammonium salts formed from any of the compounds comprising a group of N. Water soluble or oil soluble or dispersed products can be obtained by quaternization. The alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. The pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed by anti-equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, sulfonates And aromatic sulfonates.

除非其他方面表明，本发明的化合物所有的立体异构体，几何异构体， 互变异构体， 氮氧化物， 水合物， 溶剂化物， 代谢产物， 盐和药学上可接 受的前药都属于本发明的范围。  Unless otherwise indicated, all stereoisomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of the invention are It is within the scope of the invention.

具体地说， 盐是药学上可接受的盐。 术语"药学上可接受的"包括物质 或组合物必须是适合化学或毒理学地，与组成制剂的其他组分和用于治疗 的哺乳动物有关。 Specifically, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" includes the substance or composition which must be suitable for chemical or toxicological purposes, with other components of the formulation and for treatment Related to mammals.

如果本发明的化合物是碱性的，则想得到的盐可以通过文献上提供的 任何合适的方法制备得到， 例如， 使用无机酸， 如盐酸， 氢溴酸， 硫酸， 硝酸和磷酸等等。 或者使用有机酸， 如乙酸， 马来酸， 琥珀酸， 扁桃酸， 富马酸， 丙二酸， 丙酮酸， 草酸， 羟乙酸和水杨酸； 吡喃糖酸， 如葡萄糖 醛酸和半乳糖醛酸； α-羟酸， 如柠檬酸和酒石酸； 氨基酸， 如天门冬氨酸 和谷氨酸； 芳香族酸，如苯曱酸和肉桂酸；磺酸，如对曱苯橫酸， 乙磺酸， 等等。  If the compound of the present invention is basic, the desired salt can be prepared by any suitable method provided in the literature, for example, using a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like. Or use organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid and salicylic acid; pyranoic acid such as glucuronic acid and galactose Aldehydic acid; α-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such as p-toluic acid, ethyl sulfonate Sour, and so on.

如果本发明的化合物是酸性的，则想得到的盐可以通过合适的方法制 备得到， 如， 使用无机碱或有机碱， 如氨（伯氨， 仲氨， 叔氨）， 碱金属 氢氧化物或碱土金属氢氧化物， 等等。 合适的盐包括， 但并不限于， 从氨 基酸得到的有机盐， 如甘氨酸和精氨酸， 氨， 如伯氨、 仲氨和叔氨， 和环 状氨， 如哌啶， 吗啉和哌嗪等， 和从钠， 钙， 钾， 镁， 锰， 铁， 铜， 辞， 铝和锂得到无机盐。  If the compound of the present invention is acidic, the desired salt can be prepared by a suitable method, for example, using an inorganic base or an organic base such as ammonia (primary ammonia, secondary ammonia, tertiary ammonia), alkali metal hydroxide or alkaline earth. Metal hydroxide, and so on. Suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia such as primary, secondary and tertiary ammonia, and cyclic ammonia such as piperidine, morpholine and piperazine Etc., and get inorganic salts from sodium, calcium, potassium, magnesium, manganese, iron, copper, rhodium, aluminum and lithium.

本发明的"溶剂化物"是指一个或多个溶剂分子与本发明的化合物所 形成的締合物。 形成溶剂化物的溶剂包括， 但并不限于， 水， 异丙醇， 乙 醇， 曱醇， 二曱亚砜， 乙酸乙酯， 乙酸， 氨基乙醇。 术语"水合物"是指溶 剂分子是水所形成的締合物。  "Solvate" as used herein refers to an association of one or more solvent molecules with a compound of the invention. Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, decyl alcohol, disulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" means that the solvent molecule is an association formed by water.

本发明的化合物存在自由形态，或合适的、作为药学上可接受的衍生 物。 根据本发明， 药学上可接受的衍生物包括， 但并不限于， 药学上可接 受的前药， 盐， 酯， 酯类的盐， 或能直接或间接地根据患者的需要给药的 其他任何加合物或衍生物，本发明其他方面所描述的化合物，其代谢产物 或他的残留物。  The compounds of the invention exist in free form or, as appropriate, as pharmaceutically acceptable derivatives. According to the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of esters, or any other agent which can be administered directly or indirectly according to the needs of the patient. An adduct or derivative, a compound described in other aspects of the invention, a metabolite thereof or a residue thereof.

像本发明所描述的，本发明药学上可接受的组合物进一步包含药学上 可接受的载体，辅剂，或赋形剂，这些像本发明所应用的， 包括任何溶剂， 稀释剂， 或其他液体赋形剂， 分散剂或悬浮剂， 表面活性剂， 等渗剂， 增 稠剂， 乳化剂， 防腐剂， 固体粘合剂或润滑剂等等， 适合于特有的目标剂 型。  As described herein, the pharmaceutically acceptable compositions of the present invention further comprise a pharmaceutically acceptable carrier, adjuvant, or excipient, as used herein, including any solvent, diluent, or other Liquid excipients, dispersing or suspending agents, surfactants, isotonic agents, thickeners, emulsifiers, preservatives, solid binders or lubricants, etc., are suitable for the specific target dosage form.

可作为药学上可接受载体的物质包括，但并不限于，离子交换剂，铝， 硬脂酸铝， 卵磷脂， 血清蛋白， 如人血清蛋白， 緩沖物质如磷酸盐， 甘氨 酸， 山梨酸， 山梨酸钾， 饱和植物脂肪酸的部分甘油酯混合物， 水， 盐或 电解质， 如硫酸鱼精蛋白， 磷酸氢二钠， 磷酸氢钾， 氯化钠， 辞盐， 胶体 硅， 三硅酸镁， 聚乙烯吡咯烷酮， 聚丙烯酸脂， 蜡， 聚乙烯-聚氧丙烯-阻 断聚合体， 羊毛脂， 糖， 如乳糖， 葡萄糖和蔗糖； 淀粉如玉米淀粉和土豆 淀粉；纤维素和它的衍生物如羧曱基纤维素钠，乙基纤维素和乙酸纤维素； 树胶粉； 麦芽； 明胶； 滑石粉； 辅料如可可豆脂和栓剂蜡状物； 油如花生 油， 棉子油， 红花油， 麻油， 橄榄油， 玉米油和豆油； 二醇类化合物， 如 丙二醇和聚乙二醇； 酯类如乙基油酸酯和乙基月桂酸酯； 琼脂； 緩沖剂如 氢氧化镁和氢氧化铝； 海藻酸； 无热原的水； 等渗盐； 林格 (氏)溶液； 乙 醇,磷酸緩沖溶液,和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁， 着色剂，释放剂， 包衣衣料，甜味剂，调味剂和香料， 防腐剂和抗氧化剂。 Substances which may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, aluminum, Aluminum stearate, lecithin, serum protein, such as human serum albumin, buffer substances such as phosphate, glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated plant fatty acids, water, salt or electrolytes, such as sulphate Protein, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, salt, colloidal silicon, magnesium trisilicate, polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking polymer, lanolin , sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; gum powder; malt; gelatin; Talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycol compounds such as propylene glycol and polyethylene glycol; Such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic salts; Ethanol, phosphate buffer solution, and other non-toxic suitable lubricants such as sodium lauryl sulfate and magnesium stearate, colorants, release agents, coatings, sweeteners, flavorings and fragrances, preservatives and antioxidants; .

本发明的组合物可以是口服给药，注射给药，喷雾吸入法，局部给药， 经直肠给药， 经鼻给药， 含服给药， ***给药或通过植入性药盒给药。 此 处所使用的术语"经注射的"包括皮下的， 静脉的， 肌内的， 关节内的， 滑 膜 (腔)内的， 胸骨内的， 膜内的， 目艮内的， 肝内的， 病灶内的， 和颅内的 注射或输注技术。 优选的组合物为口服给药， 向腹膜内给药或静脉注射。 本发明的组合物无菌的注射方式可以是水的或油脂性的悬浮液。这些悬浮 液可以根据公知技术采用合适的分散剂、湿润剂和悬浮剂按配方制造。无 菌注射剂可以是无菌注射液或悬浮液,是注射无毒的可接受的稀释剂或溶 剂， 如 1,3-丁二醇溶液。 这些可接受的赋形剂和溶剂可以是水， 林格溶液 和等渗氯化钠溶液。更进一步地，无菌的非挥发性的油按照惯例可以作为 溶剂或悬浮介质。  The composition of the present invention may be administered orally, by injection, by inhalation, topically, rectally, nasally, buccally, vaginally or via an implantable kit. . The term "injected" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, synovial (cavity), intrasternal, intramembranous, intraocular, intrahepatic, Intralesional, and intracranial injection or infusion techniques. A preferred composition is for oral administration, either intraperitoneally or intravenously. The sterile injectable form of the compositions of the present invention may be a watery or oleaginous suspension. These suspensions may be formulated according to known techniques using suitable dispersing, wetting and suspending agents. The sterile injectable preparation may be a sterile injectable solution or suspension, and is a non-toxic acceptable diluent or solvent, such as a 1,3-butanediol solution. These acceptable excipients and solvents can be water, Ringer's solution and isotonic sodium chloride solution. Further, sterile, non-volatile oils are conventionally employed as a solvent or suspending medium.

以此为目的，任何温和的非挥发性的油可以是合成的单或二葡基甘油 二酯。 脂肪酸， 如油酸和它的甘油酯衍生物可用于血管注射剂的制备，作 为天然的药学上可接受的油脂，如橄榄油或蓖麻油，特别是它们的聚氧乙 烯衍生物。这些油溶液或悬浮液可以包含长链醇稀释剂或分散剂，如羧曱 基纤维素或相似分散剂，一般用于药学上可接受剂型的药物制剂包括乳化 液和悬浮液。 其他常用的表面活性剂， 如吐温类， 司盘类和其他乳化剂或 生物药效率的强化剂，一般用于药学上可接受的固体，液体，或其他剂型， 并可以应用于目标药物制剂的制备。 For this purpose, any mild non-volatile oil can be a synthetic mono or di-glycosyl diglyceride. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially their polyoxyethylene derivatives. These oil solutions or suspensions may contain long-chain alcohol diluents or dispersing agents, such as carboxymethylcellulose or similar dispersing agents, and pharmaceutical preparations which are generally used in pharmaceutically acceptable dosage forms include emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifiers or Bioavailability enhancers are generally used in pharmaceutically acceptable solid, liquid, or other dosage forms and can be applied to the preparation of a pharmaceutical formulation of interest.

本发明药学上可接受的组合物可以是以任何可接受的口服剂型进行 口服给药， 其中包括， 但并不限于， 胶嚢， 片剂， 水制悬浮液或溶液。 关 于片剂口服使用， 载体一般包括乳糖和玉米淀粉。 润滑剂， 如硬脂酸镁， 都典型地被添加。对于胶嚢口服给药，合适的稀释剂包括乳糖和干的玉米 淀粉。 当口服给药为水制悬浮液时， 其有效成分由乳化剂和悬浮剂组成。 如果想得到这些剂型， 某些甜味剂、 调味剂或着色剂也可以被添加。  The pharmaceutically acceptable compositions of this invention may be orally administered in any acceptable oral dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. For oral administration to tablets, the carriers generally include lactose and corn starch. Lubricants, such as magnesium stearate, are typically added. For oral administration to capsules, suitable diluents include lactose and dried corn starch. When orally administered as an aqueous suspension, the active ingredient consists of an emulsifier and a suspending agent. If these dosage forms are desired, certain sweeteners, flavoring or coloring agents may also be added.

另夕卜，本发明药学上可接受的组合物可以以栓剂的形式直肠给药。这 些可以通过将试剂与合适的非灌注辅药混合制备而成，这种辅药在室温下 为固体但在直肠的温度下则为液体，从而在直肠中熔化并释放药物。这样 的物质包括可可豆脂，蜂蜡， 和聚乙二醇类。 本发明药学上可接受的组合 物可以是局部给药，特别是局部用药时， 涉及到区域或器官的治疗目标容 易达到， 如眼、皮肤或下肠道的疾病。合适的局部用药制剂可以制备得到 并应用于这些领域或器官。  Further, the pharmaceutically acceptable composition of the present invention can be administered rectally in the form of a suppository. These can be prepared by mixing the agent with a suitable non-perfused adjuvant which is solid at room temperature but liquid at the temperature of the rectum to melt and release the drug in the rectum. Such materials include cocoa butter, beeswax, and polyethylene glycols. The pharmaceutically acceptable compositions of the present invention may be administered topically, especially in the case of topical administration, involving the treatment of a region or organ, such as an eye, skin or lower intestinal tract. Suitable topical formulations can be prepared and applied to these fields or organs.

直肠栓剂（见以上内容）或合适的灌肠剂可以应用于下部肠道的局部 用药。局部皮肤斑也可以这样用药。对于局部用药， 药学上可接受的组合 物可以按制剂方法制备成合适的软膏，该软膏包含活性成分悬浮于或溶解 于一个或多个载体。本发明局部给药的载体化合物包括，但并不限于矿物 油， 液体石蜡， 白凡士林， 丙二醇， 聚氧乙烯， 聚氧丙烯化合物， 乳化蜡 和水。 另外， 药学上可接受的组合物可以制备成合适的洗剂或乳剂 ， 该 洗剂或乳剂包含活性成分悬浮于或溶于一个或多个药学上可接受的载体。 合适的载体包括， 但并不限于， 矿物油， 司盘 -60 (脱水山梨醇单硬脂酸 酯） ， 吐温 60 (聚山梨酯 60 ) , 十六烷基酯蜡， 棕榈醇， 2-辛基十二烷 醇， 苯曱醇和水。  Rectal suppositories (see above) or suitable enema agents can be applied topically to the lower intestinal tract. Local skin spots can also be used as such. For topical administration, the pharmaceutically acceptable compositions can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carrier compounds for topical administration of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions may be prepared as a suitable lotion or emulsion containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, Span-60 (sorbitan monostearate), Tween 60 (polysorbate 60), cetyl ester wax, palmitol, 2- Octyl dodecanol, phenylhydrin and water.

对于眼用的、药学上可接受的组合物可以制备成制剂，如等渗的微粒 化悬浮液， pH调节的无菌盐水或其他水溶液， 优选地， 等渗溶液和 pH 调节的无菌盐水或其他水溶液， 可以添加消毒防腐剂如苯扎氯铵。 另外， 对于眼用的，药学上可接受的组合物可以按制剂配方制备成软膏如凡士林 油。 本发明药学上可接受的组合物可以通过鼻的气溶剂或吸入剂进行给 药。这样的组合物可以根据制剂配方的公知技术制备得到，或可以制备成 盐溶液， 使用苯曱醇或其他合适的防腐剂、 吸收促进剂、碳氟化合物或其 他常规增溶剂或分散剂来提高生物利用度。 For ophthalmic, pharmaceutically acceptable compositions can be prepared as preparations, such as isotonic microparticulate suspensions, pH adjusted sterile saline or other aqueous solutions, preferably, isotonic solutions and pH adjusted sterile saline or For other aqueous solutions, a disinfectant preservative such as benzalkonium chloride may be added. In addition, for ophthalmic use, the pharmaceutically acceptable composition can be prepared into an ointment such as petrolatum according to the formulation of the preparation. Oil. The pharmaceutically acceptable compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to well-known techniques of formulation formulations, or may be prepared as a salt solution, using benzoquinone or other suitable preservatives, absorption enhancers, fluorocarbons or other conventional solubilizing or dispersing agents to enhance the organism. Utilization.

口服给药的液体剂型包括，但并不限于， 药学上可接受的乳剂， 微乳 剂， 溶液， 悬浮液， 糖浆剂和酏剂。 除活性化合物外， 液体剂型可以包含 公知的一般的惰性稀释剂， 例如， 水或其他溶剂， 增溶剂和乳化剂， 如乙 醇， 异丙醇， 碳酸乙酯， 乙酸乙酯， 苯曱醇， 苯曱酸苄酯， 丙二醇， 1,3- 丁二醇， 二曱基曱酰胺， 油脂（特别是棉籽， 落花生， 玉米， 微生物， 橄 榄， 蓖麻和麻油） ， 甘油， 2-四氢呋喃曱醇， 聚乙二醇， 去水山梨糖醇脂 肪酸酯， 以及它们的混合物。 除惰性的稀释剂之外， 口服组合物也可以包 含辅剂如湿润剂， 乳化剂或悬浮剂， 甜味剂， 调味剂和芳香剂。  Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. The liquid dosage form may contain, in addition to the active compound, a conventional inert diluent such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzoquinone, benzene. Benzyl phthalate, propylene glycol, 1,3-butanediol, dimercaptoamide, oils (especially cottonseed, groundnut, corn, microbes, olives, ramie and sesame oil), glycerol, 2-tetrahydrofuranol, poly Ethylene glycol, sorbitan fatty acid esters, and mixtures thereof. Besides the inert diluent, the oral compositions may also contain adjuvants such as wetting agents, emulsifying or suspending agents, sweetening agents, flavoring agents and perfuming agents.

口服给药的固体剂型包括胶嚢， 片剂， 丸剂， 粉剂和粒剂。 在这些剂 型中，活性化合物与至少一种药学上可接受的惰性赋形剂或载体混合，如 柠檬酸钠或磷酸 4弓或充填剂或 a)填充剂如淀粉， 乳糖， 蔗糖， 葡萄糖， 甘露醇和硅酸， b)粘合剂如羧曱基纤维素， 藻酸盐， 明胶， 聚乙烯吡咯酮， 蔗糖和***胶， c)保湿剂如甘油， d)崩解剂如琼脂， 碳酸 4弓， 土豆淀粉 或木薯淀粉， 海藻酸， 某些硅酸盐和碳酸钠， e)阻滞剂溶液如石蜡， f)吸收 促进剂如季胺类化合物， g)湿润剂如十六醇和单硬脂酸甘油酯， h)吸收剂 如白陶土和皂土， i)润滑剂如滑石粉， 硬脂酸 4丐， 硬脂酸镁， 固体聚乙二 醇， 月桂硫酸钠， 及它们的混合物。 至于胶嚢， 片剂和丸剂， 这些剂型可 以包含緩沖剂。  Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or phosphate 4 or a filler or a) a filler such as starch, lactose, sucrose, glucose, mannose Alcohol and silicic acid, b) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar, carbonic acid 4 bow , potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) retarder solutions such as paraffin, f) absorption enhancers such as quaternary amines, g) wetting agents such as cetyl alcohol and monostearate Acid glycerides, h) absorbents such as kaolin and bentonite, i) lubricants such as talc, 4% stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. As for capsules, tablets and pills, these dosage forms may contain buffers.

注射剂，如无菌注射液或油脂性的悬浮液可以根据公知技术采用合适 的分散剂、湿润剂和悬浮剂按制剂配方制备得到。无菌注射剂可以是无毒 的经注射地可接受的稀释剂或溶剂制成的无菌注射液、悬浮液或乳液，例 如， 1,3-丁二醇溶液。 可接受的赋形剂和溶剂可以是水， 林格 (氏)溶液， U.S.P.和等渗氯化钠溶液。 另外， 无菌的非挥发性的油按照惯例作为溶剂 或悬浮介质。以此为目的任何温和的非挥发性的油可以包括合成的单或二 葡基甘油二酯。 另外， 脂肪酸如油酸可以应用于注射剂。 注射剂可以是无菌的，如通过细菌防卫过滤器过滤，或以无菌固体组 合物的形式掺入灭菌剂，在使用前灭菌剂可以溶解于或分散于消毒水或其 他无菌注射介质中。为了延长本发明的化合物的效果，通常需要通过皮下 注射或肌内注射来减緩化合物的吸收。这样可以实现利用液体悬浮液解决 晶体或非晶体物质水溶性差的问题。 化合物的吸收率取决于它的溶出度， 依次取决于晶粒大小和晶体形状。另外，可以通过化合物在油类赋形剂中 溶解或分散来完成化合物注射给药的延迟吸收。 An injection, such as a sterile injectable solution or a oleaginous suspension, can be prepared according to the known formulation using suitable dispersing agents, wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in the form of a non-toxic injectable acceptable diluent or solvent, for example, a 1,3-butanediol solution. Acceptable excipients and solvents can be water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile, non-volatile oils are conventionally employed as a solvent or suspending medium. Any mild non-volatile oil for this purpose may include synthetic mono- or di-glycosyl diglycerides. In addition, fatty acids such as oleic acid find use in injections. The injection may be sterile, such as by filtration through a bacterial defense filter, or by incorporating a sterilizing agent in the form of a sterile solid composition, which may be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. in. In order to prolong the effects of the compounds of the invention, it is usually necessary to slow the absorption of the compound by subcutaneous or intramuscular injection. This makes it possible to solve the problem of poor water solubility of crystalline or amorphous materials by using a liquid suspension. The rate of absorption of a compound depends on its dissolution, which in turn depends on the grain size and crystal shape. In addition, delayed absorption of the compound injection administration can be accomplished by dissolving or dispersing the compound in an oil vehicle.

本发明的化合物优选地按制剂配方制备成剂量单位型以减轻给药量 和剂量的均勾性。术语"剂量单位型 "在此处是指患者得到适当治疗所需药 物的物理分散单位。然而，应了解本发明的化合物或组合物每日总的用法 将通过主治医生根据可靠的医学范围判断来确定。具体的有效剂量水平对 于任何一个特殊的患者或有机体将取决于许多因素包括被治疗的病症和 病症的严重性， 具体化合物的活性， 所用的具体组合物， 患者的年龄、 体 重、 健康状况、 性别和饮食习惯， 给药时间， 给药途径和所用具体化合物 的***速率，治疗的持续时间， 药物应用于联合用药或与有特效的化合物 联用， 以及其他一些药学领域公知的因素。  The compounds of the present invention are preferably prepared in dosage unit form in a formulation to reduce the amount of administration and the uniformity of the dosage. The term "dosage unit type" as used herein refers to the physically discrete unit of the drug required for the patient to receive appropriate treatment. However, it is to be understood that the total daily usage of the compounds or compositions of the present invention will be determined by the attending physician based on a reliable medical field judgment. The specific effective dosage level for any particular patient or organism will depend on a number of factors including the severity of the condition and condition being treated, the activity of the particular compound, the particular composition employed, the patient's age, weight, health, sex And dietary habits, time of administration, route of administration and excretion rate of the particular compound employed, duration of treatment, administration of the drug in combination or in combination with a compound having a specific effect, and other factors well known in the pharmaceutical arts.

本发明同样包含所述的化合物或所述的药物组合物治疗与受体酪氨 酸蛋白激酶有关疾病的方法，包括给予患者所述化合物或所述的药物组合 物的有效治疗量。此方法包括本发明的化合物或组合物与细胞接触，从而 抑制细胞生长。能被抑制生长的细胞包括：乳腺癌细胞，结肠直肠癌细胞， 肺癌细胞， ***状癌细胞， ***癌细胞， 淋巴瘤细胞， 结肠癌细胞， 胰 腺癌细胞， 卵巢癌细胞， 子***细胞， 中枢神经***癌细胞， 成骨肉瘤 细胞， 肾癌细胞， 肝细胞癌细胞， 膀胱癌细胞， 胃癌细胞， 头或颈鳞癌细 胞， 黑色素瘤细胞和白血病细胞。  The invention likewise encompasses a method of treating a disease associated with a receptor tyrosine kinase comprising a compound or a pharmaceutical composition comprising administering to the patient a therapeutically effective amount of the compound or the pharmaceutical composition. This method involves contacting a compound or composition of the invention with a cell to inhibit cell growth. Cells that can be inhibited from growth include: breast cancer cells, colorectal cancer cells, lung cancer cells, papillary cancer cells, prostate cancer cells, lymphoma cells, colon cancer cells, pancreatic cancer cells, ovarian cancer cells, cervical cancer cells, Central nervous system cancer cells, osteosarcoma cells, renal cancer cells, hepatocellular carcinoma cells, bladder cancer cells, gastric cancer cells, head or cervical squamous cell carcinoma cells, melanoma cells and leukemia cells.

本发明的化合物或药学上可接受的组合物的"有效量 "或"有效剂量" 是指处理或减轻一个或多个本发明所提到病症的严重度的有效量。根据本 发明的方法，化合物和组合物可以是任何给药量和任何给药途径来有效地 用于处理或减轻疾病的严重程度。必需的准确的量将根据患者的情况而改 变， 这取决于种族， 年龄， 患者的一般条件， 感染的严重程度， 特殊的因 素， 给药方式， 等等。化合物或组合物可以和一个或多个其他治疗剂联合 给药， 如本发明所讨论的。 具体实施方式 An "effective amount" or "effective amount" of a compound or pharmaceutically acceptable composition of the invention refers to an effective amount to treat or ameliorate the severity of one or more of the conditions mentioned herein. In accordance with the methods of the present invention, the compounds and compositions can be administered in any amount and in any route of administration effective to treat or reduce the severity of the disease. The exact amount required will vary depending on the patient's condition, depending on race, age, general condition of the patient, severity of infection, specific cause , the mode of administration, and so on. The compound or composition can be administered in combination with one or more other therapeutic agents, as discussed herein. detailed description

为了进一步了解本发明，下面结合实施例对本发明优选实施方案进行 描述， 但是应当理解， 这些描述只是为进一步说明本发明的特征和优点， 而不是对本发明权利要求的限制。  In order to further understand the invention, the preferred embodiments of the present invention are described in the accompanying drawings.

以下以具体实施例说明本发明的效果，但本发明的保护范围不受以下 实施例的限制。  The effects of the present invention are described below by way of specific examples, but the scope of the present invention is not limited by the following examples.

下面结合具体实验例， 进一步阐述本发明。 应该理解， 这些实施例 仅用于举例说明本发明， 而不是用来限制本发明的范围。 下列条件， 实施 例如为注明具体实验方法，通常按照常规，或按照制造厂家所建议的条件。 化合物制备  The present invention will be further illustrated below in conjunction with specific experimental examples. It is to be understood that the examples are not intended to limit the scope of the invention. The following conditions are implemented, for example, to indicate the specific experimental method, usually as usual, or in accordance with the conditions recommended by the manufacturer. Compound preparation

化合物的结构是通过核磁共振（ NMR )和质谱（ MS )来确定的。 NMR 位移 （δ )是以百万分之一 ( ppm )单位给出。 NMR谱图的测定是用 Bruker-300核磁仪。  The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) is given in parts per million (ppm). The NMR spectrum was measured using a Bruker-300 nuclear magnetic instrument.

MS的测定是用 Agilent LC-MS ( ESI+ )质语仪。  The MS was assayed using an Agilent LC-MS (ESI+) grammar.

如无特别说明， 反应均在氮气氛下进行。  Unless otherwise stated, the reactions were all carried out under a nitrogen atmosphere.

柱层析和薄板层析均使用 Merck生产的硅胶和硅胶层析板。  Both column chromatography and thin plate chromatography were performed using silica gel and silica gel chromatography plates manufactured by Merck.

实施例 1 :  Example 1

(E)-N-(7-((3R,3aS,6S,6aS)-六氢 -3-曱氧基呋喃 [3,2-b]呋喃 -6-基氧 基)—4- ( 3-氯 -4-氟苯胺基 )喹唑啉 -6-基 -4- (二曱基胺基 )丁 -2-烯酰胺的制 备

(E)-N-(7-((3R,3aS,6S,6aS)-hexahydro-3-indolylfuran[3,2-b]furan-6-yloxy)-4- ( 3- Preparation of chloro-4-fluoroanilinoquinazolin-6-yl-4-(didecylamino)but-2-enamide

步骤一 step one

N- ( 3-氯 -4-氟苯基） -7-(((3R,3aS,6S,6aS)-6-曱氧基六氢呋喃 [3,2-b] 呋喃 -3-基)氧基) -6-硝基喹唑啉 -4-胺（lb ) 的制备：  N-(3-chloro-4-fluorophenyl)-7-(((3R,3aS,6S,6aS)-6-decyloxyhexahydrofuran[3,2-b]furan-3-yl)oxy Preparation of -6-nitroquinazolin-4-amine (lb):

在室温下和氮气环境中， 向良好搅拌的 -D-glucitol (1.5 g, 10.26 mmol) 的无水二曱基曱酰胺 （20 mL)溶液中分批量加入氢化钠 （60 % 混在 矿 物油中， 493 mg, 12.32 mmol)。 20分钟后， 向反应液中滴加人曱基換 (639 μΐ,, 10.26 mmol)。 再过 30分钟， 反应液被冷却到 0^oC, 向其中再加入氢 化钠 （60 % 混在 矿物油中， 493 mg, 12.32 mmol)。 过 20分钟， N- ( 3-氯 -4-氟苯基) -7-氟 -6-硝基喹唑啉 -4-胺（la, 制备参照： Smaill, J.B., et al" Journal of Medicinal Chemistry, 2000, 43 , p. 1380 - 1397 )。 反应搅拌 30 分钟后， 在 0^oC向其加入饱和 NH₄C1水溶液（ 20 mL ), 所得混合物用乙 酸乙酯（ 100 mL )萃取。 所得有机层再用水（ 100 mL ) 洗 2次， 饱和盐 水洗一次，用硫酸镁干燥，滤去固体，真空旋转蒸发抽干，得到黄色固体, N- ( 3-氯 -4-氟苯基） -7-(((3R,3aS,6S,6aS)-6-曱氧基六氢呋喃 [3,2-b]呋喃 -3- 基)氧基) -6-硝基喹唑啉 -4-胺（lb )。 产物直接用于下一步反应。 To a well-stirred solution of -D-glucitol (1.5 g, 10.26 mmol) in anhydrous dihydrazinamide (20 mL) at rt (60%) 493 mg, 12.32 mmol). After 20 minutes, a human thiol group (639 μΐ, 10.26 mmol) was added dropwise to the reaction solution. After an additional 30 minutes. The reaction solution was cooled to 0 ^o C, and thereto was added sodium hydride (60% in mineral oil mixture, 493 mg, 12.32 mmol). After 20 minutes, N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (la, Preparation Reference: Smaill, JB, et al" Journal of Medicinal Chemistry , 2000, 43 , p. 1380 - 1397 ). After stirring for 30 minutes, a saturated aqueous solution of NH ₄ C1 (20 mL) was then added at 0 ^o C, and the mixture was extracted with ethyl acetate (100 mL). The mixture was washed twice with water (100 mL), EtOAc (EtOAc) (((3R,3aS,6S,6aS)-6-decyloxyhexahydrofuran[3,2-b]furan-3-yl)oxy)-6-nitroquinazolin-4-amine (lb The product was used directly in the next reaction.

质谱： MS m/z(ESI+): 477 [M+1]  Mass Spectrum: MS m/z (ESI+): 477 [M+1]

步骤二  Step two

N⁴- ( 3-氯 -4-氟苯基） -7-(((3R,3aS,6S,6aS)- 6-曱氧基六氢呋喃 [3,2-b] 呋喃 -3-基)氧基)-喹唑啉 -3-基)氧基） 喹唑啉 -4,6-二胺（lc) 的制备 N ⁴ -( 3-chloro-4-fluorophenyl)-7-(((3R,3aS,6S,6aS)-6-methoxyhexahydrofuran [3,2-b] Preparation of furan-3-yl)oxy)-quinazolin-3-yl)oxy)quinazoline-4,6-diamine (lc)

N- -chloro-A-fluorophenyD- - Si^ai^R^ai ^-methoxyhexahydrofur o[3,2-b]furan-3-yl)oxy)quinazoline-4,6-diamine (lc): N--chloro-A-fluorophenyD- - Si^ai^R^ai ^-methoxyhexahydrofur o[3,2-b]furan-3-yl)oxy)quinazoline-4,6-diamine (lc):

向搅拌中的化合物 lb(700 mg, 1.47 mmol)的乙醇 /水（ 2/1 )溶液（ 90 mL )加入冰乙酸（ 3 mL ), 然后再加入铁粉（ 328 mg, 5.87 mmol )。 混合 物加热回流 1小时，然后冷却到室温。向反应液中慢慢加入氢氧化钠水溶 液（ 5M ), 直到反应液的 pH值达到 7-8。 反应用乙酸乙酯（ 100 mL )稀 释， 并强力搅拌 30 分钟。反应混合物经硅藻土过滤， 并用乙酸乙酯（100 mL) 洗 2次。 滤液真空旋转蒸干后， 再加入水（100 mL), 并用二氯曱 烷 /曱醇（9/1, 100 mL)萃取 2次。 有机层合在一起， 用硫酸镁干燥， 滤去干燥剂， 真空旋转蒸干后得到黄绿色的固体： N⁴- (3-氯 -4-氟苯胺基） -7-(((3R,3aS,6S,6aS)- 6-曱氧基六氢呋喃 [3,2-b]呋喃 -3-基)氧基)-喹唑啉 -3- 基)氧基） 喹唑啉 -4,6-二胺（lc)。 产物直接用于下一步反应。 To a stirred solution of compound lb (700 mg, 1.47 mmol) in ethanol/water (2/1) (90 mL) was added glacial acetic acid (3 mL) and then iron powder ( 328 mg, 5.87 mmol). The mixture was heated to reflux for 1 hour and then cooled to room temperature. Aqueous sodium hydroxide solution (5 M) was slowly added to the reaction solution until the pH of the reaction solution reached 7-8. The reaction was diluted with ethyl acetate (100 mL) and stirred vigorously for 30 min. The reaction mixture was filtered through EtOAc (EtOAc)EtOAc. After the filtrate was evaporated to dryness in vacuo, water (100 mL) was then taken and extracted twice with dichloromethane/nonyl alcohol (9/1, 100 mL). The organic layers are combined, dried over magnesium sulfate, filtered to remove the desiccant, and evaporated to dryness in vacuo to give a yellow-green solid: N ⁴ - (3-chloro-4-fluoroanilinyl) -7- ((3R, 3aS) ,6S,6aS)- 6-decyloxyhexahydrofuran[3,2-b]furan-3-yl)oxy)-quinazolin-3-yl)oxy)quinazoline-4,6- Diamine (lc). The product was used directly in the next reaction.

质谱： MSm/z(ESI+): 447 [M+1] 步骤三  Mass Spectrum: MSm/z (ESI+): 447 [M+1] Step 3

二乙基 (2- ((4- (3-氯 -4-氟苯基） -7-(((3R,3aS,6S,6aS)- 6-曱氧基六 氢呋喃 [3,2-b]呋喃 -3-基)氧基) -喹唑啉 -3-基)氧基） 喹唑啉 -6-基）胺 -2-羰乙 基）磷酸酯（Id) 的制备  Diethyl(2-((4-chloro-4-fluorophenyl)-7-(((3R,3aS,6S,6aS)-6-decyloxyhexahydrofuran [3,2-b] Preparation of furan-3-yl)oxy)-quinazolin-3-yl)oxy)quinazolin-6-yl)amine-2-carbonylethyl)phosphate (Id)

Diethyl(2-((4-(3-chloro-4-fluorophenyl)-7-(((35,3a5,6R,6a5)-6-metho xyhexahydrofuro[3,2-b]furan-3-yl)oxy)quinazolin-6-yl)amino-2-oxoethyl) phosphonate:  Diethyl(2-((4-(3-chloro-4-fluorophenyl)-7-(((35,3a5,6R,6a5)-6-metho xyhexahydrofuro[3,2-b]furan-3-yl)oxy )quinazolin-6-yl)amino-2-oxoethyl) phosphonate:

1,1-羰基二咪唑 （ CDI, 310 mg, 1.91 mmol ) 和二乙基膦乙酸 ( diethylphosphonoacetic acid, 375 mg, 1.91 mmol ) 混合在无水四氩 ^{P P}南 (THF, 10 mL) 中， 加热到 40 °C并搅拌 30分钟。 向该反应中加入化合 物 lc ( 657 mg, 1.47 mmol ) 的 THF溶液（ 3 mL )。 反应在 45 °C下搅拌 16小时。 反应用乙酸乙酯（lOOmL)稀释， 用饱和碳酸氢钠 （lOOmL), 水（lOOmL), 饱和盐水（ lOOmL)洗。 有机层用硫酸镁干燥， 滤去干燥 剂， 真空旋转蒸干后得到二乙基 （ 2- ( ( 4- ( 3-氯 -4-氟苯基 ) -7-(((3R,3aS,6S,6aS)- 6-曱氧基六氢呋喃 [3,2-b]呋喃 -3-基)氧基)-喹唑啉 -3- 基)氧基） 喹唑啉 -6-基）胺 -2-羰乙基）磷酸酯 （ld )。 产物直接用于下一 步反应。 1,1-Carbonyldiimidazole (CDI, 310 mg, 1.91 mmol) and diethylphosphonoacetic acid (375 mg, 1.91 mmol) were mixed in anhydrous tetra-argon ^PP (THF, 10 mL) and heated to Stir at 40 °C for 30 minutes. To the reaction was added a solution of compound lc (657 mg, 1.47 mmol) in THF (3 mL). The reaction was stirred at 45 ° C for 16 hours. The reaction was diluted with ethyl acetate (100 mL) and washed with saturated sodium hydrogen sulfate (lOOmL), water (lOOmL) and saturated brine (100 mL). The organic layer was dried over magnesium sulfate and filtered to dry The solvent is evaporated to dryness in vacuo to give diethyl(2-(4-(3-chloro-4-fluorophenyl)-7-(((3R,3aS,6S,6aS)-6-methoxy) Hydrogen [5,2-b]furan-3-yl)oxy)-quinazolin-3-yl)oxy) quinazolin-6-yl)amine-2-carbonylethyl)phosphate (ld ). The product was used directly in the next reaction.

质谱： MS m/z(ESI+): 625 [M+1] 步骤四  Mass Spectrum: MS m/z (ESI+): 625 [M+1] Step 4

(E)-N-(7-((3R,3aS,6S,6aS)-六氢 -3-曱氧基呋喃 [3,2-b]呋喃 -6-基氧 基)—4- ( 3-氯 -4-氟苯胺基 )喹唑啉 -6-基 -4- (二曱基胺基 )丁 -2-烯酰胺 ( 1 ) 的制备  (E)-N-(7-((3R,3aS,6S,6aS)-hexahydro-3-indolylfuran[3,2-b]furan-6-yloxy)-4- ( 3- Preparation of chloro-4-fluoroanilinoquinazolin-6-yl-4-(didecylamino)but-2-enamide (1)

(£)-N-(4-((3-chloro-4-fluorophenyl)-7-(((35,3a5,6R,6a5)-6-methoxyhe xahydrofuro[3,2-b]furan-3-yl)oxy)quinazolin-6-yl)-4-(dimethylamino) but-2-enamide:  (£)-N-(4-((3-chloro-4-fluorophenyl)-7-(((35,3a5,6R,6a5)-6-methoxyhe xahydrofuro[3,2-b]furan-3-yl )oxy)quinazolin-6-yl)-4-(dimethylamino) but-2-enamide:

在室温下， 向化合物 Id ( 400 mg, 0.64 mmol )在乙醇（ 10 mL )的溶 液中加入氯化锂（ 105 mg, 1.28 mmol ),然后加入 45%的氢氧化钾（ 1 mL )。 5分钟后，向反应液中加入 2-二曱胺乙醛 -亚疏酸氢盐（ 214 mg, 1.28 mmol, 制备方法参照： WO2007/85638 )。搅拌 15分钟后，再用二氯曱烷（ 200 mL ) 稀释反应， 用水（ 100 mL ) 洗 2次， 饱和盐水（ 100 mL ) 洗 1次。 有机 层用硫酸镁干燥，滤去干燥剂，真空旋转蒸干后得到的产物用柱层析分离 ( 0-20%曱醇 /二氯曱烷）得到 （E)-N-(7-((3R,3aS,6S,6aS)-六氢 -3-曱氧基呋 喃 [3,2-b]呋喃 -6-基氧基 )-4- ( 3-氯 -4-氟苯胺基）喹唑啉 -6-基 -4- (二曱基胺 基）丁 -2-烯酰胺（1 )。  To a solution of the compound Id (400 mg, 0.64 mmol) in ethanol (10 mL) was added lithium chloride (105 mg, 1.28 mmol) and then 45% potassium hydroxide (1 mL). After 5 minutes, 2-diamine acetaldehyde-hydrochlorite (214 mg, 1.28 mmol, preparation method: WO2007/85638) was added to the reaction mixture. After stirring for 15 minutes, the reaction was diluted with dichloromethane (200 mL), washed twice with water (100 mL) and once with saturated brine (100 mL). The organic layer was dried over magnesium sulfate, and the dried solvent was filtered off, and then evaporated to dryness in vacuo to give the product (0-20% methanol/dichloromethane) to give (E)-N-(7-(( 3R,3aS,6S,6aS)-Hexahydro-3-indolylfuran[3,2-b]furan-6-yloxy)-4-(3-chloro-4-fluoroanilino)quinazoline -6-yl-4-(didecylamino)but-2-enamide (1).

核磁： ifiNMR (CDC1₃, 300 MHz) 9.16 (s, 1H), 8.66 (s, 1H), 8.04 (s, 1H), 7.90 (d, 1H), 7.75 (s, 1H), 7.56 (m, 1H), 7.40 (s, 1H), 7.17 (m, 1H), 7.06 (m, 1H), 6.25 (d, 1H), 5.05 (s, 1H), 4.85 (t, 1H), 4.74 (d, 1H), 4.32 (m, 2H), 4.01 (m, 2H), 3.78 (t, 1H), 3.54 (s, 2H), 3.20 (d, 2H), 2.35 (s, 6H). Nuclear magnetic: ifiNMR (CDC1 ₃ , 300 MHz) 9.16 (s, 1H), 8.66 (s, 1H), 8.04 (s, 1H), 7.90 (d, 1H), 7.75 (s, 1H), 7.56 (m, 1H) ), 7.40 (s, 1H), 7.17 (m, 1H), 7.06 (m, 1H), 6.25 (d, 1H), 5.05 (s, 1H), 4.85 (t, 1H), 4.74 (d, 1H) , 4.32 (m, 2H), 4.01 (m, 2H), 3.78 (t, 1H), 3.54 (s, 2H), 3.20 (d, 2H), 2.35 (s, 6H).

质谱： MS (ESI) m/z = 559 (MH⁺). 实施例 2: Mass Spectrum: MS (ESI) m/z = 559 (MH ⁺ ). Example 2:

(E)-N-(7-((3-醚双环 [3· 1 ·0]己烷 -6-基）曱氧基 )-4-((3-氯 -4-氟苯基)胺基 ) 喹唑啉 -6-基 -4- (二曱基胺基）丁 -2-烯酰胺的制备  (E)-N-(7-((3-Etherbicyclo[3·1·0]hexane-6-yl)decyloxy)-4-((3-chloro-4-fluorophenyl)amino) Preparation of quinazolin-6-yl-4-(didecylamino)but-2-enamide

(£')-N-(7-((3-oxabicyclo[3.1.0]hexan-6-ylmethoxy)-4-((3-chloro-4-fluo rophenyl)amino)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide  (£')-N-(7-((3-oxabicyclo[3.1.0]hexan-6-ylmethoxy)-4-((3-chloro-4-fluo rophenyl)amino)quinazolin-6-yl)-4 -(dimethylamino)but-2-enamide

步骤一 step one

7—((3-醚双环 [3.1.0]己烷 -6-基)曱氧基) -N-(3-氯 -4-氟苯基 )-6-硝基喹唑 啉—4—胺（2b ) 的制备：  7-((3-Etherbicyclo[3.1.0]hexane-6-yl)decyloxy)-N-(3-chloro-4-fluorophenyl)-6-nitroquinazoline-4-amine Preparation of (2b):

7- ((3 -oxa-bicy clo [3.1.0]hexan-6-yl)methoxy)-N-(3-chloro-4-fluoropheny l)-6-nitroquinazolin-4-amine  7-((3 -oxa-bicy clo [3.1.0]hexan-6-yl)methoxy)-N-(3-chloro-4-fluoropheny l)-6-nitroquinazolin-4-amine

在 0^oC下， 向良好搅拌的 (3-醚双环 [3,2-0]己烷 -6-基）曱醇 (1.5 g, 10.26 mmol, 2a 制备参照： US2008/249087 ) 的无水二曱基曱酰胺 （²0 mL)溶液 中分批量加入氢化钠 （60 % 混在 矿物油中， ⁴93 mg, l².3² mmol)。 过 ²0 分钟， N- ( 3-氯 -4-氟苯基） -7-氟 -6-硝基喹唑啉 -4-胺（la )。 反应搅拌 30 分钟后， 在 0^oC向其加入饱和 NH₄C1水溶液（ 20 mL ), 所得混合物用乙 酸乙酯（lOO mL )萃取。 所得有机层再用水（lOO mL ) 洗 2次， 饱和盐 水洗一次，用硫酸镁干燥，滤去固体，真空旋转蒸发抽干，得到黄色固体， 7—((3-醚双环 [3.1.0]己烷-6-基）曱氧基)- (3-氯-4-氟苯基)-6-硝基喹唑啉-4- 胺（2b )。 产物直接用于下一步反应。 To a well-stirred (3-ether bicyclo[3,2-0]hexane-6-yl) decyl alcohol (1.5 g, 10.26 mmol, 2a, reference: US2008/249087) at 0 ^o C Yue Yue amide group ⁽² 0 mL) was added sodium hydride equatorial batch (mixed 60% in mineral ^{oil, 4 93 mg, l 2 .3} 2 mmol). After ²⁰ minutes, N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (la). After stirring for 30 minutes, and extracted with ethyl acetate (lOO mL) was added thereto at 0 ^o C with saturated aqueous NH ₄ C1 (20 mL), the resulting mixture. The obtained organic layer was washed twice with water (100 mL), EtOAc (EtOAc) Hexane-6-yl)nonyloxy)-(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4- Amine (2b). The product was used directly in the next reaction.

质谱： MS m/z(ESI+): 43 1 [M+1] 步骤二、 三和四：  Mass Spectrum: MS m/z (ESI+): 43 1 [M+1] Steps 2, 3, and 4:

(E)-N-(7-((3-醚双环 [3.1.0]己烷 -6-基)曱氧基 )-4-((3-氯 -4-氟苯基)胺基 ) 喹唑啉 -6-基 -4- (二曱基胺基）丁 -2-烯酰胺的制备  (E)-N-(7-((3-Etherbicyclo[3.1.0]hexane-6-yl)decyloxy)-4-((3-chloro-4-fluorophenyl)amino) quin Preparation of oxazoline-6-yl-4-(didecylamino)but-2-enamide

(£')-N-(7-((3-oxabicyclo[3.1.0]hexan-6-yl)methoxy)-4-((3-chloro-4-fluorop henyl)amino)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide。 (£')-N-(7-((3-oxabicyclo[3.1.0]hexan-6-yl)methoxy)-4-((3-chloro-4-fluorop henyl)amino)quinazolin-6-yl) -4-(dimethylamino)but-2-enamide.

应用实施例 1中完全一样的步骤二、 三和四， 将化合物 2b转变成： (E)-N-(7-((3-醚双环 [3.1.0]己烷 -6-基)曱氧基) -4-((3-氯 -4-氟苯基)胺基）喹唑 啉—6—基—4- (二曱基胺基）丁 -2-烯酰胺（2 )。  Using the exact same steps 2, 3 and 4 in Example 1, the compound 2b was converted to: (E)-N-(7-((3-etherbicyclo[3.1.0]hexane-6-yl)oxime) -4-((3-Chloro-4-fluorophenyl)amino)quinazoline-6-yl-4-(didecylamino)but-2-enamide (2).

核磁： ifiNMR (CDC1₃, 300 MHz) 9.17 (s, IH), 8.66 (s, IH), 8.17 (s, IH), 7.96 (m, IH), 7.75 (s, IH), 7.56 (m, IH), 7.22 (s, IH), 7.16 (m, IH), 7.05 (m, IH), 6.25 (d, IH), 4.16 (d, IH), 4.02 (d, IH), 3.79 (d, IH), 3.20 (d, IH), 2.35 (s, 4H), 1.78 (s, 2H), 1.73 (s, 6H), 1.47 (m, IH). Nuclear magnetic: ifiNMR (CDC1 ₃ , 300 MHz) 9.17 (s, IH), 8.66 (s, IH), 8.17 (s, IH), 7.96 (m, IH), 7.75 (s, IH), 7.56 (m, IH) ), 7.22 (s, IH), 7.16 (m, IH), 7.05 (m, IH), 6.25 (d, IH), 4.16 (d, IH), 4.02 (d, IH), 3.79 (d, IH) , 3.20 (d, IH), 2.35 (s, 4H), 1.78 (s, 2H), 1.73 (s, 6H), 1.47 (m, IH).

质谱： MS (ESI) m/z = 513 (M+1). 实施例 3  Mass Spectrum: MS (ESI) m/z = 513 (M+1). Example 3

(E)-N-(7-((l 5S)-3-醚双环 [3.1.0]己烷-1-基)曱氧基)-4-((3-氯-4-氟苯 基)胺基）喹唑啉 -6-基 -4- (二曱基胺基）丁 -2-烯酰胺的制备  (E)-N-(7-((5S)-3-etherbicyclo[3.1.0]hexane-1-yl)decyloxy)-4-((3-chloro-4-fluorophenyl) Preparation of Amino)quinazolin-6-yl-4-(didecylamino)but-2-enamide

( )-N-(7-((15,55)-3-oxabicyclo[3.1.0]hexan-l-yl)methoxy)-4-((3-chloro-4-fl uorophenyl)amino)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide ( )-N-(7-((15,55)-3-oxabicyclo[3.1.0]hexan-l-yl)methoxy)-4-((3-chloro-4-fl uorophenyl)amino)quinazolin-6 -yl)-4-(dimethylamino)but-2-enamide

步骤一 step one

(\R,5S)-l- ((苄氧基) 曱基） -3-醚 -双环 [3.1.0]己烷 -2-酮 (3b ) 的制 备  Preparation of (\R,5S)-l-((benzyloxy)indolyl)-3-ether-bicyclo[3.1.0]hexane-2-one (3b)

(lR,5S)-l-((benzyloxy)methyl)-3-oxa-bicyclo[3.1.0]hexan-2-one 在 0^QC下， 向搅拌中的（1R,5 -1- (羟基曱基 -3-醚 -双环 [3,2-0]己烷 -2- 酉同（ 3a, 100 mmol, l备参照、 Moon, H.R., et al. Nucleosides, Nucleotides and Nucleic Acids, 2007 , 26, p.975 - 978 ) THF (200 mL)溶液中分批量加 入氢化钠 （60% 混在 矿物油中， 4.80 mg, 120 mmol)。 10分钟后， 加入苄 基溴（ 120 mmol )。 反应在室温下搅拌 12小时后， 被冷却到 0^QC, 并向反 应中加入饱和 N C1水溶液（ 50mL )和水（ 50mL ), 所得混合物用*** ( 300 mL )萃取。 所得有机层再用水（lOOmL) 洗 1次， 饱和盐水洗一 次， 用硫酸镁干燥， 滤去固体， 真空旋转蒸发抽干， 所得液体用柱层析分 离 （0-20%乙酸乙酯 /己烷）给出无色液体， 为纯的 1R,5 -1- ((苄氧基） 曱基 -3-醚 -双环 [3.1.0]己烷 -2-酮 ( 3b ) 质谱： MS (ESI) m/z = 219 (M+l). 步骤二 (lR,5S)-l-((benzyloxy)methyl)-3-oxa-bicyclo[3.1.0]hexan-2-one at 0 ^Q C, stirring (1R,5 -1-(hydroxyindole) 3-ether-bicyclo[3,2-0]hexane-2-indole (3a, 100 mmol, l reference, Moon, HR, et al. Nucleosides, Nucleotides and Nucleic Acids, 2007, 26, p .975 - 978 ) Add sodium hydride (60% in mineral oil, 4.80 mg, 120 mmol) in THF (200 mL). After 10 min, add benzyl bromide (120 mmol). After 12 hours, it was cooled to 0 ^Q C, and a saturated aqueous solution of N.sub.1 (50 mL) and water (50 mL) was added to the mixture, and the mixture was extracted with diethyl ether (300 mL). The obtained organic layer was washed once with water (100 mL) Wash once with saturated brine, dry over magnesium sulfate, EtOAc (EtOAc). ,5 -1- ((benzyloxy) decyl-3-ether-bicyclo[3.1.0]hexane-2-one (3b) Mass Spectrum: MS (ESI) m/z = 219 (M+l). Step 2

(1S,55)-1- ( (苄氧基) 曱基） -3-醚 -双环 [3.1.0]己烷 ( 3c )  (1S,55)-1-((benzyloxy)indolyl)-3-ether-bicyclo[3.1.0]hexane (3c)

该制备方法参照： Sakai, N., et al. Synthesis, 2008 p. 3533— 3536。 向 1 5 -1-((苄氧基）曱基)-3-醚-双环[3.1.0]己烷-2-酮（31) , 50 mmol ) 与三溴化铟（ 1.Ommol )在氯仿（ 200 mL )的混合物中加入三乙基硅烷（ 200 mmol )。 所得混合物加热到 65^QC, 并在 16小时后冷却到室温。 反应在真 空旋转蒸发抽干， 所得液体用柱层析分离（0-10%乙酸乙酯 /己烷）给出无 色液体， 为纯的（1S,5 -1- ( (苄氧基) 曱基） -3-醚 -双环 [3.1.0]己烷 ( 3c ) 质谱： MS (ESI) m/z = 205 (M+l). 步骤三 This preparation method is referred to: Sakai, N., et al. Synthesis, 2008 p. 3533-3536. To 1 5 -1-((benzyloxy)indolyl)-3-ether-bicyclo[3.1.0]hexane-2-one (31), 50 mmol) with indium tribromide (1.0 mmol) Triethylsilane (200 mmol) was added to a mixture of chloroform (200 mL). The resulting mixture was heated to 65 ^Q C and cooled to room temperature after 16 hours. The reaction was evaporated to dryness in vacuo. EtOAc (EtOAc: EtOAc) 3-ether-bicyclo[3.1.0]hexane (3c) Mass Spectrum: MS (ESI) m/z = 205 (M+l). Step 3

( (lR,5 -3-醚 -双环 [3.1.0]己烷 -1-基） 曱醇 (3d)  ((lR,5 -3-ether-bicyclo[3.1.0]hexane-1-yl) decyl alcohol (3d)

((lR,5S)-3-oxa-bicyclo[3.1.0]hexan-l-yl)methanol  ((lR,5S)-3-oxa-bicyclo[3.1.0]hexan-l-yl)methanol

(1S,55)-1- ( (苄氧基) 曱基） -3-醚 -双环 [3.1.0]己烷 ( 3c, 40 mmol )和 钯-碳（5% )在曱醇 (50 mL) 中的混合物用氢气球氢化 3小时。 混合物经 硅藻土过滤， 小心真空旋转蒸发抽干 （水浴温度保持在 25^GC以下）。 所 得化合物为无色液体， （(lR,5S)-3-醚 -双环 [3.1.0]己烷-1-基）曱醇， 直接用 于下一步反应。 步骤四、 五、 六和七 (1S,55)-1-((benzyloxy)indolyl)-3-ether-bicyclo[3.1.0]hexane (3c, 40 mmol) and palladium-carbon (5%) in furfuryl alcohol (50 mL) The mixture in the mixture was hydrogenated with a hydrogen balloon for 3 hours. The mixture was filtered through celite and carefully dried with vacuum rotary evaporation (water bath temperature was kept below 25 ^G C). The obtained compound was a colorless liquid ((lR,5S)-3-ether-bicyclo[3.1.0]hexane-1-yl)nonanol, which was directly used for the next reaction. Steps four, five, six and seven

(E)-N-(7-((l 5S)-3-醚双环 [3丄0]己烷 -1-基)曱氧基 )-4-((3-氯 -4-氟苯 基)胺基）喹唑啉 -6-基 -4- (二曱基胺基）丁 -2-烯酰胺 ( 3 ) 的制备  (E)-N-(7-((5S)-3-etherbicyclo[3丄0]hexane-1-yl)decyloxy)-4-((3-chloro-4-fluorophenyl) Preparation of Amino)quinazolin-6-yl-4-(didecylamino)but-2-enamide (3)

(E)-N-(7-(((lS,5S)-3-oxa-bicyclo[3.1.0]hexan-l-yl)methoxy)-4-(3-chloro -4-fluorophenylamino)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide  (E)-N-(7-(((S),5S)-3-oxa-bicyclo[3.1.0]hexan-l-yl)methoxy)-4-(3-chloro-4-fluorophenylamino)quinazolin-6 -yl)-4-(dimethylamino)but-2-enamide

实施例 3中的步骤四、 五、 六和七和实施例 2中步骤一、 二、 三和四 完全相同， 只是将化合物 2a换成化合物 3d , 从而得到 (E)-N-(7-((l 5S)- 醚双环 [3.1.0]己烷 - 1 -基)曱氧基) -4-((3-氯 -4-氟苯基)胺基 )喹唑啉—6-基 -4- (二曱基胺基） 丁 -2-烯酰胺（3 )。 Steps 4, 5, 6 and 7 in Example 3 are identical to steps 1, 2, 3 and 4 in Example 2 except that compound 2a is replaced by compound 3d to give (E)-N-(7-( (l 5S)-Etherbicyclo[3.1.0]hexane- 1 -yl)decyloxy)-4-((3-chloro-4-fluorophenyl)amino)quinazoline-6-yl-4 - (Didecylamino)but-2-enamide (3).

核磁： ifiNMR (CD₃OD, 300 MHz) 8.78 (s, IH), 8.48 (s, IH), 8.01 (m_: IH), 7.67 (m, IH), 7.25 (m, 2H), 7.01 (m, IH), 6.47 (d, IH), 4.62 (s, IH), 4.53 (d, IH), 4.37 (d, IH), 4.01 (d, IH), 3.85 (m, 2H), 3.24 (d, 2H), 2.34 (s, 6H), 1.77 (m, IH), 1.29 (s, IH), 1.00 (m, IH), 0.79 (m, IH), 0.11 (s, IH). Nuclear magnetic: ifiNMR (CD ₃ OD, 300 MHz) 8.78 (s, IH), 8.48 (s, IH), 8.01 (m _: IH), 7.67 (m, IH), 7.25 (m, 2H), 7.01 (m, IH), 6.47 (d, IH), 4.62 (s, IH), 4.53 (d, IH), 4.37 (d, IH), 4.01 (d, IH), 3.85 (m, 2H), 3.24 (d, 2H ), 2.34 (s, 6H), 1.77 (m, IH), 1.29 (s, IH), 1.00 (m, IH), 0.79 (m, IH), 0.11 (s, IH).

质谱： MS (ESI) m/z = 513 (M+l). 实施例 4  Mass Spectrum: MS (ESI) m/z = 513 (M+l). Example 4

(E)-N-(7-((lR,5R)-3-醚双环 [3· 1 ·0]己烷 -1-基)曱氧基 )-4-((3-氯 -4-氟苯基） 胺基）喹唑啉 -6-基 -4- (二曱基胺基）丁 -2-烯酰胺的制备  (E)-N-(7-((lR,5R)-3-etherbicyclo[3·1·0]hexane-1-yl)decyloxy)-4-((3-chloro-4-fluoro) Preparation of phenyl)amino)quinazolin-6-yl-4-(didecylamino)but-2-enamide

(£)-N-(7-((lR,5R)-3-oxabicyclo[3.1.0]hexan-l-yl)methoxy)-4-((3-chloro -4-fluorophenyl)amino)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide  (£)-N-(7-((lR,5R)-3-oxabicyclo[3.1.0]hexan-l-yl)methoxy)-4-((3-chloro-4-fluorophenyl)amino)quinazolin-6 -yl)-4-(dimethylamino)but-2-enamide

实施例 4是用实施例 3制备方法完全相同的方法和步骤来合成，只是 用 （1&5R)-1- (羟基曱基 -3-醚 -双环 [3,2-0]己烷 -2-酮（4a )来代替 (1R,5 - 1- (羟基曱基 -3-醚 -双环 [3,2-0]己烷 -2-酮 ( 3a )。  Example 4 was synthesized by the same method and procedure as the preparation method of Example 3 except that (1&5R)-1-(hydroxyindolyl-3-ether-bicyclo[3,2-0]hexan-2-one was used. (4a) is substituted for (1R,5- 1-(hydroxyindolyl-3-ether-bicyclo[3,2-0]hexane-2-one (3a).

核磁： ifiNMR (CD₃OD, 300 MHz) 8.78 (s, IH), 8.48 (s, IH), 8.01 (m_: IH), 7.67 (m, IH), 7.25 (m, 2H), 7.01 (m, IH), 6.47 (d, IH), 4.62 (s, IH), 4.53 (d, IH), 4.37 (d, IH), 4.01 (d, IH), 3.85 (m, 2H), 3.24 (d, 2H), 2.34 (s, 6H), 1.77 (m, IH), 1.29 (s, IH), 1.00 (m, IH), 0.79 (m, IH), 0.11 (s, IH). Nuclear magnetic: ifiNMR (CD ₃ OD, 300 MHz) 8.78 (s, IH), 8.48 (s, IH), 8.01 (m _: IH), 7.67 (m, IH), 7.25 (m, 2H), 7.01 (m, IH), 6.47 (d, IH), 4.62 (s, IH), 4.53 (d, IH), 4.37 (d, IH), 4.01 (d, IH), 3.85 (m, 2H), 3.24 (d, 2H ), 2.34 (s, 6H), 1.77 (m, IH), 1.29 (s, IH), 1.00 (m, IH), 0.79 (m, IH), 0.11 (s, IH).

质谱： MS (ESI) m/z = 513 (M+l). 实施例 5 Mass Spectrum: MS (ESI) m/z = 513 (M+l). Example 5

(土) -(E)-N-(7-((3-醚双环 [3.1.0]己烷-1-基)曱氧基)-4-((3-氯-4-氟苯基)胺 基）喹唑啉—6-基 -4- (二曱基胺基） 丁 -2-烯酰胺 ( 5 ) 的制备  (soil) -(E)-N-(7-((3-etherbicyclo[3.1.0]hexane-1-yl)decyloxy)-4-((3-chloro-4-fluorophenyl) Preparation of Amino)quinazoline-6-yl-4-(didecylamino)but-2-enamide (5)

(±)-(E)-N-(7-((3-oxa-bicyclo[3.1.0]hexan-l-yl)methoxy)-4-(3-chloro-4-f uorophenylamino uinazolin-6-yl)-4-(dimethylamino)but-2-enamide  (±)-(E)-N-(7-((3-oxa-bicyclo[3.1.0]hexan-l-yl)methoxy)-4-(3-chloro-4-f uorophenylamino uinazolin-6-yl )-4-(dimethylamino)but-2-enamide

实施例 5是用实施例 3制备方法完全相同的方法和步骤来合成，只是 用 (±)-1- (羟基曱基 -3-醚 -双环 [3,2-0]己烷 -2-酮 （5a )来代替 (1R,5 -1- (羟基曱基 -3-醚 -双环 [3,2-0]己烷 -2-酮 ( 3a )  Example 5 was synthesized by the same method and procedure as the preparation method of Example 3 except that (±)-1-(hydroxyindolyl-3-ether-bicyclo[3,2-0]hexan-2-one was used. (5a) instead of (1R,5 -1-(hydroxyindolyl-3-ether-bicyclo[3,2-0]hexan-2-one (3a)

核磁： ifiNMR (CD₃OD, 300 MHz) 8.78 (s, IH), 8.48 (s, IH), 8.01 (m_: IH), 7.67 (m, IH), 7.25 (m, 2H), 7.01 (m, IH), 6.47 (d, IH), 4.62 (s, IH), 4.53 (d, IH), 4.37 (d, IH), 4.01 (d, IH), 3.85 (m, 2H), 3.24 (d, 2H), 2.34 (s, 6H), 1.77 (m, IH), 1.29 (s, IH), 1.00 (m, IH), 0.79 (m, IH), 0.11 (s, IH). Nuclear magnetic: ifiNMR (CD ₃ OD, 300 MHz) 8.78 (s, IH), 8.48 (s, IH), 8.01 (m _: IH), 7.67 (m, IH), 7.25 (m, 2H), 7.01 (m, IH), 6.47 (d, IH), 4.62 (s, IH), 4.53 (d, IH), 4.37 (d, IH), 4.01 (d, IH), 3.85 (m, 2H), 3.24 (d, 2H ), 2.34 (s, 6H), 1.77 (m, IH), 1.29 (s, IH), 1.00 (m, IH), 0.79 (m, IH), 0.11 (s, IH).

质谱： MS (ESI) m/z = 513 (M+l). 实施例 6  Mass Spectrum: MS (ESI) m/z = 513 (M+l). Example 6

激酶活性抑制实验  Kinase activity inhibition assay

1 ) 化合物溶解在 DMSO中配成 10 mM浓度溶液。 然后用水稀释到 1) The compound was dissolved in DMSO to prepare a 10 mM solution. Then diluted with water to

100 uM浓度， 作为起始浓度， 再每次稀释 10倍用于 IC₅。测定。 均相时间 分辨荧光 HTIU 技术被用来检测分析激酶活性的抑制。 A concentration of 100 uM was used as the starting concentration and diluted 10 times for IC ₅ each time. Determination. A homogeneous time-resolved fluorescent HTIU technique was used to detect inhibition of assay kinase activity.

2 ) 在 384孔板上， 化合物和相应的激酶一起培养 30分钟。 然后激酶 底物和 ATP加入孔中开始反应。 15分钟后， 检测试剂 Sa-XL665和检测 抗体 TK Ab-Cryptate力口入孔中， 停止反应。 3 ) 将 384孔板封上， 并在室温下培养 1小时。 在 620nM ( Cryptate ) 和 665nM(XL655)频率检测荧光强度。 2) Compounds were incubated with the corresponding kinase for 30 minutes in a 384-well plate. The kinase substrate and ATP are then added to the wells to initiate the reaction. After 15 minutes, the detection reagent Sa-XL665 and the detection antibody TK Ab-Cryptate were inserted into the wells to stop the reaction. 3) The 384-well plate was sealed and incubated for 1 hour at room temperature. Fluorescence intensities were measured at 620 nM (Cryptate) and 665 nM (XL655) frequencies.

4) 每个浓度同时在 3个孔中重复检测， 未加化合物的孔作为阴性控 制， 同时用已知化合物作为阳性控制。  4) Each concentration was repeatedly tested in 3 wells, and the unconjugated well was used as a negative control, with known compounds as positive control.

数据分析处理： 计算出 620nM ( Cryptate )和 665nM(XL655)的 ( 665/620 )。 结果由此计算： 信号强度 = 药物荧光强度比例 - 阴性控制 荧光强度比例。 IC₅。是通过浓度 -抑制曲线计算得到。 Data analysis processing: Calculated (620/620) of 620 nM (Cryptate) and 665 nM (XL655). The results are calculated from this: Signal strength = drug fluorescence intensity ratio - negative control fluorescence intensity ratio. IC ₅ . It is calculated by the concentration-inhibition curve.

表 2、 本发明所述化合物激酶活性抑制实验及细胞株增殖抑制实验结果  Table 2. Inhibition experiments of the kinase activity of the compounds of the present invention and the results of cell proliferation inhibition experiments

由上表可见， 本发明所列化合物对 EGFr和 Her2激酶抑制的 IC₅。 均 小于 100nM。 实施例 7

The above table shows, the compounds of the invention listed EGFr and Her2 kinase inhibition IC _5. Both are less than 100nM. Example 7

对 BT474细胞株增殖抑制。  Inhibition of proliferation of BT474 cell line.

1 ) 在 96孔板上， 每孔植入 10,000个 BT474细胞， 再在 37 ^QC培养 24小时。 1) On a 96-well plate, 10,000 BT474 cells were implanted per well and cultured at 37 ^Q C for 24 hours.

2 ) 将不同浓度的化合物加入孔中 （ 30 M到 0.16 nM, 每次 5倍稀 释） ， 在完全的细胞培养液中培养 72小时。  2) Add different concentrations of compounds to the wells (30 M to 0.16 nM, 5 times dilution) and incubate in complete cell culture for 72 hours.

3 ) 除去细胞培养液， 用 CCK-8试剂检测细胞。  3) Remove the cell culture medium and measure the cells with CCK-8 reagent.

4 ) 计算出浓度 -生长曲线，并用此曲线计算细胞株增殖抑制的 EC₅。值。 4) Calculate the concentration - growth curve, this curve is calculated and used to suppress cell proliferation of EC _5. value.

结果见表 2,显示本发明所列化合物对 BT474细胞增殖抑制 EC₅。 均 小于 100nM。 本发明提出的已通过实施例进行了描述，相关技术人员明显能在不脱 离本发明内容、精神和范围内对本文所述的石墨烯的制备方法进行改动或 适当变更与组合， 来实现本发明技术。 特别需要指出的是， 所有相类似的 替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本 发明的精神、 范围和内容中。 The results in Table 2, the compounds listed in the display of the present invention inhibit the proliferation of BT474 cells EC _5. Both are less than 100nM. The present invention has been described by way of example, and it is obvious to those skilled in the art that the present invention can be modified or combined and modified to achieve the present invention without departing from the scope, spirit and scope of the present invention. technology. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the spirit, scope and content of the invention.

Claims

权 利 要 求 Rights request

1 式（I )所示化合

1 Formula (I)

式 ( I )  Formula ( I )

或其立体异构体、 几何异构体、 互变异构体、 水合物、 溶剂化物、 多 晶型物、 代谢产物、 药学上可接受的盐或前药， 其中：  Or a stereoisomer, geometric isomer, tautomer, hydrate, solvate, polymorph, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:

Ar是被取代的单环苯基或单环芳香杂环基， 可以被 0-4个卤素， 三 氟曱基， 三氟曱氧基， C_1-3烷基所取代， 乙炔基， 乙婦基， C_1-3烷氧基， 或 O CH^Ar¹所取代， 其中 n是 0或 1 ; Ar is a substituted monocyclic phenyl or monocyclic aromatic heterocyclic group which may be substituted by 0-4 halogen, trifluoromethyl, trifluoromethoxy, C _1-3 alkyl, ethynyl, a group, C _1-3 alkoxy, or O CH^Ar ¹ substituted, wherein n is 0 or 1;

Ar¹选自单环芳香环或 5-6元芳香杂环， 并且芳香环或芳香杂环可以 被 0-3个卤素， 三氟曱基， 三氟曱氧基， C_1-3烷基所取代， C_2-3炔基， C_2-3 烯基， C_w烷氧基所取代； Ar ^{1 is} selected from a monocyclic aromatic ring or a 5-6 membered aromatic heterocyclic ring, and the aromatic ring or the aromatic heterocyclic ring may be 0-3 halogen, trifluorodecyl, trifluoromethoxy, C _1-3 alkyl Substituted, C _2-3 alkynyl, C _2-3 alkenyl, C _w alkoxy;

L选自单键或 CH₂; L is selected from a single bond or CH ₂ ;

M是一个 6-10元双环烷基杂环， 杂环内含一个或多个 0, N, 或 S 原子， 并且杂环上可以进一步被一个或多个卤素， d_₃烷基， 羟基， 或 烷氧基所取代。 M is a 6-10 membered bicycloalkyl heterocycle containing one or more 0, N, or S atoms, and the heterocycle may be further substituted with one or more halogens, d- ₃ alkyl, hydroxy, or Substituted by an alkoxy group.

2、 根据权利要求 1所述的化合物， 其特征在于， Ar选自以下结构 式： 2. The compound according to claim 1, wherein Ar is selected from the following structural formula:

根据权利要求 1所述的化合物， 其特征在于， 其具有以下之一的  The compound according to claim 1, which has one of the following

4、 根据权利要求 1所述的化合物， 其特征在于， 所述药学上可接 受的盐为上述化合物与以下的酸形成的盐： 苹果酸， 乳酸， 马来酸， 富马 酸， 琥珀酸， 盐酸， 曱橫酸， 曱苯橫酸， 苯橫酸， 硫酸， 磷酸， 柠檬酸, 酒石酸， 乙酸， 丙酸， 辛酸， 己酸， 苯曱酸。 The compound according to claim 1, wherein the pharmaceutically acceptable salt is a salt of the above compound with an acid: malic acid, lactic acid, maleic acid, fumaric acid, succinic acid, Hydrochloric acid, hydrazine acid, terpene phthalic acid, benzoic acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, acetic acid, propionic acid, caprylic acid, caproic acid, benzoic acid.

5、 一种药物组合物， 包含根据权利要求 1所述的化合物或其立体异 构体、 几何异构体、 互变异构体、 水合物、 溶剂化物、 多晶型物、 代谢产 物、 药学上可接受的盐或前药， 及其药学上可接受的载体， 赋形剂， 稀释 剂， 辅剂， 媒介物， 或它们的组合。 5. A pharmaceutical composition comprising the compound according to claim 1 or a stereoisomeric thereof a construct, a geometric isomer, a tautomer, a hydrate, a solvate, a polymorph, a metabolite, a pharmaceutically acceptable salt or a prodrug, and a pharmaceutically acceptable carrier thereof, an excipient , diluent, adjuvant, vehicle, or a combination thereof.

6、 权利要求 1-4任一项所述化合物或权利要求 5所述药物组合物在 制备治疗与受体酪氨酸蛋白激酶有关疾病的药物或受体酪氨酸蛋白激酶 抑制剂的用途。  6. Use of a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 for the preparation of a medicament or a receptor tyrosine protein kinase inhibitor for the treatment of a disease associated with a receptor tyrosine protein kinase.

7、 根据权利要求 6所述的用途， 其特征在于， 所述受体酪氨酸蛋白 激酶有关疾病包括但不限于： 乳腺癌， 结肠直肠癌， 肺癌， ***状癌， 前 列腺癌， 淋巴瘤， 结肠癌， 胰腺癌， 卵巢癌， 子***， 中枢神经***癌， 成骨肉瘤， 肾癌， 肝癌， 膀胱癌， 胃癌， 头或颈鳞癌， 黑色素瘤和白血病。  7. The use according to claim 6, wherein the receptor tyrosine protein kinase-related diseases include, but are not limited to, breast cancer, colorectal cancer, lung cancer, papillary carcinoma, prostate cancer, lymphoma, Colon cancer, pancreatic cancer, ovarian cancer, cervical cancer, central nervous system cancer, osteosarcoma, kidney cancer, liver cancer, bladder cancer, gastric cancer, head or neck squamous cell carcinoma, melanoma and leukemia.

8、 一种使用权利要求 1所述的化合物或权利要求 5所述的药物组合 物治疗与受体酪氨酸蛋白激酶有关疾病的方法，包括给予患者如权利要求 1所述化合物或权利要求 5所述的药物组合物的有效治疗量。  8. A method of treating a disease associated with a receptor tyrosine protein kinase using the compound of claim 1 or the pharmaceutical composition of claim 5, comprising administering to a patient a compound of claim 1 or claim 5 An effective therapeutic amount of the pharmaceutical composition.

9、 权利要求 1所述化合物的制备方法， 包括下列步骤：  9. A method of preparing a compound of claim 1 comprising the steps of:

步骤 1 :化合物 la与苯胺化合物 ArNH₂进行取代反应得到化合物 lb; 步骤 2: 醇 M—L—OH用强碱处理后加入化合物 lb得到化合物 Ic; 步骤 3: 化合物 Ic发生还原反应生成 Id; Step 1: Compound la is substituted with the aniline compound ArNH ₂ to obtain compound lb; Step 2: The alcohol M-L-OH is treated with a strong base and then compound lb is added to obtain compound Ic; Step 3: Compound Ic is reduced to form Id;

步骤 4: Id与酸 Ie偶联试剂作用下进行酰胺化反应生成化合物 If; 步骤 5: 化合物 If 和 2-二曱胺乙醛进行维悌希反应生成通式（I )化 合物；

其中， Ar是被取代的单环苯基或单环芳香杂环基， 可以被 0-4个卤 素， 三氟曱基， 三氟曱氧基， C_1-3烷基所取代， 乙炔基， 乙烯基， C_1-3烷 氧基， 或 O CH^Ar¹所取代， 其中 n是 0或 1 ; Step 4: Id is reacted with an acid Ie coupling reagent to form a compound If; Step 5: Compound If and 2-diamine acetaldehyde are subjected to a Wittig reaction to form a compound of the formula (I);

Wherein Ar is a substituted monocyclic phenyl or monocyclic aromatic heterocyclic group which may be substituted by 0-4 halogen, trifluoromethyl, trifluoromethoxy, C _1-3 alkyl, ethynyl, Substituted by a vinyl group, a C _1-3 alkoxy group, or O CH^Ar ¹ wherein n is 0 or 1;

Ar¹选自单环芳香环或 5-6元芳香杂环， 并且芳香环或芳香杂环可以 被 0-3个卤素， 三氟曱基， 三氟曱氧基， C_1-3烷基所取代， C_2-3炔基， C_2-3 烯基， C_w烷氧基所取代； Ar ^{1 is} selected from a monocyclic aromatic ring or a 5-6 membered aromatic heterocyclic ring, and the aromatic ring or the aromatic heterocyclic ring may be 0-3 halogen, trifluorodecyl, trifluoromethoxy, C _1-3 alkyl Substituted, C _2-3 alkynyl, C _2-3 alkenyl, C _w alkoxy;

L选自单键或 CH₂; L is selected from a single bond or CH ₂ ;

M是一个 6-10元双环烷基杂环， 杂环内含一个或多个 0, N, 或 S 原子， 并且杂环上可以进一步被一个或多个卤素， d_₃烷基， 羟基， 或 烷氧基所取代。 M is a 6-10 membered bicycloalkyl heterocycle containing one or more 0, N, or S atoms, and the heterocycle may be further substituted with one or more halogens, d- ₃ alkyl, hydroxy, or Substituted by an alkoxy group.

10、根据权利要求 9所述的制备方法， 其特征在于， 步骤 2所述强碱 为氢化钠。  The preparation method according to claim 9, wherein the strong base in the step 2 is sodium hydride.

11、根据权利要求 9所述的制备方法， 其特征在于， 步骤 3所述还原 为铂-碳催化氢化， 铁粉-酸催化。  The preparation method according to claim 9, wherein the reduction in step 3 is platinum-carbon catalytic hydrogenation, iron powder-acid catalysis.